BR112020011880A2 - compound, pharmaceutical and combination compositions, process for preparing a pharmaceutical composition, use of a compound, method of treating and/or preventing a disease or condition associated with v1a receptor function, and combination. - Google Patents

Abstract

the present invention relates to 5,6-dihydro-4h-[1,2,4]triazolo[4,3-a][1]benzazepine derivatives of general formula (i) and/or salts thereof and/or geometric isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active metabolites thereof and/or prodrugs thereof and/or solvates thereof and/or hydrates thereof and/or polymorphs thereof which are central and/or peripherally acting v1a receptor modulators, particularly v1a receptor antagonists. Additional subject matter of the present invention relates to the process for preparing the compounds, as well as the intermediates of the preparation process. the invention also relates to pharmaceutical compositions containing the compounds or together with one or more other active substances, as well as their use in the treatment and/or prophylaxis of a disease or condition associated with v1a receptor function.

Description

COMPOUND, PHARMACEUTICAL AND COMBINATION COMPOSITIONS, PROCESS FOR THE PREPARATION OF A PHARMACEUTICAL COMPOSITION, USE OF A COMPOUND, METHOD FOR TREATMENT AND/OR PREVENTION OF A DISEASE OR CONDITION ASSOCIATED WITH ROUTE RECEIVER FUNCTION, AND, COMBINATION FIELD OF THE INVENTION

[001] The present invention relates to 5,6-dihydro-4H-[1,2A]triazolo[4,3-a][1]|benzazepine derivatives of general formula (I) and/or salts thereof and/or geometric isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active metabolites thereof and/or prodrugs thereof and/or solvates thereof and/or hydrates thereof and/or polymorphs thereof which are centrally and/or peripherally acting Vla receptor modulators, particularly Vla receptor antagonists. Additional subject matter of the present invention is the process for preparing the compounds as well as the intermediates of the preparation process. The invention also relates to pharmaceutical compositions containing compounds and the use thereof in the treatment and/or prophylaxis of a disease or condition associated with VIIa receptor function.

FUNDAMENTALS OF THE INVENTION

[002] Vasopressin (antidiuretic hormone, ADH, CYIQNCPRG) is a 9-amino acid peptide hormone produced by the magnocellular neurons of the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus and secreted directly into the posterior lobe of the pituitary gland where the hormone is stored until it enters the bloodstream. In the periphery, the main role of vasopressin is in the contraction of blood vessels, as well as in glucose metabolism and in the regulation of excretion.

[003] For this reason, conditions due to inappropriate secretion of vasopressin, so lack of vasopressin can lead to pathological changes in the body, such as in the central form of diabetes insipidus or abnormally low blood pressure (hypotension), whereas in cases of elevated levels of vasopressin or exogenous administration, various ways of strengthening aggressive behavior can be observed (Ferris et al., BMC Neuroscience 2008, 9:111).

[004] Oxytocin (OXT, CYIQNCPLG) is a vasopressin-related peptide hormone, differing by one amino acid and its receptor is also related to vasopressin receptors. The effects of compounds on the oxytocin receptor show species-specific differences, but the oxytocin hormone itself is identical in different mammalian species. Similarly, the vasopressin peptide is the same in all mammals (except marsupials and swine) and the effects exerted through its receptors may also show species-specific differences. The anxiolytic effect of oxytocin exerted on the central nervous system is well known (Neumann ID. J Neuroendocrinol 2008, 20(6): 858-65), thus inhibition of the oxytocin receptor in the central nervous system can trigger anxiety as an undesirable side effect.

[005] Vasopressin receptors are distinct, all are G protein-coupled receptors. The Vla receptor (VlaR) is expressed centrally in the cerebral cortex, hippocampus and pituitary gland, even more peripherally in the liver, vascular smooth muscle, lung, uterus and testicles. (Frank et al., Eur J Pharmacol 2008, 583:226-42 ). V1b receptors (VIbR) can also be found in the cortex, hippocampus and pituitary gland, and in the periphery they play an important role in regulating the pancreas and adrenal glands. In contrast to this, the V2 receptor (V2R) is mainly located in the periphery and in the kidneys, where it enhances water reabsorption, thus exerting the antidiuretic effect of vasopressin.

(Robben et al., Am J Physiol Renal Physiol 2007, 292(1): F253-60 ). Thus, due to changes in water balance regulation, the effect on the V2 receptor can cause an undesirable side effect.

[006] The secondary signaling pathways of Vla and V1b receptors include changing intracellular Ca** concentration via phosphatidylinositol, while V2 receptors activate the enzyme adenylate cyclase and influence CAMP levels (Gouzenes et al., J Physiol 1999, 517(Pt3):771-9; Tahara et al., Pflugers Arch 1999, 437(2):219-26 ).

[007] An important role is attached to Vla receptors in the regulation of the circadian rhythm. One-third of neurons in the suprachiasmatic nucleus (SCN) express vasopressin and Vla receptor MRNA exhibit daily fluctuations in this region of the brain of which the greatest values can be observed during nighttime hours (de Vries and Miller, Prog Brain Res 1998, 119: 3-20). Vasopressin shows sexual dimorphism by inducing behavioral effects, despite the fact that distribution and amount of V1aR MRNAs are not different in men and women (Szot et al., Brain Res Mol Brain Res 1994, 24(1-4):1- 10). Experiments in mice demonstrated that increased water uptake before their sleep period was triggered by their internal clock rather than their physiological needs (Gizowski et al., Nature 2016, 537(7622):685-8). Sleep disturbance is a major symptom accompanying autism (Glickman, Neurosci Biobehav Rev 2010, 34(5):755-68).

[008] Vasopressin acts as a neuromodulator in the brain, its elevated level can be detected in the amygdala under stress (Ebner et al., Eur J Neurosci 2002, 15(2):384-8). Such stressful life situations are well known to increase the possibility of developing depression and anxiety (Kendler et al., Arch Gen Psychiatry 2003, 60(8):789-96; Simon et al., Recent Pat CNS Drug Discov, 2008, 3(2):77-93; Egashira et al., J Pharmacol Sci 2009, 109(1):44-9; Bielsky et al., Neuropsychopharmacology

2004, 29(3):483-93 ). VlaR expression is elevated in the brain, especially in certain parts of the limbic system such as the amygdala, lateral septum and hippocampus that play an important role in the development of anxiety. Male mice knocked out in the VlaR gene exhibited reduced anxiety in the elevated positive maze tests, in the open field, and in dark-light boxes, but these differences could not be detected in females (Bielsky et al., Behav Brain Res 2005, 164(1) ):132-6).

[009] The male mice knocked out VlaR did not show any phenotypic difference in motor performances. In normal light-dark cycle experiments, KO VIaR mice showed no difference compared to wild-type pups, however, in experiments performed in continuous darkness, the diurnal rhythm of Vla knockout mice was significantly changed (Egashira et al. , Behav Brain Res 2007, 178(1):123-7 ).

[0010] The VlaR KO mice showed modified activity in the pre-impulse inhibition test, in the test that is accepted as an animal model of sensory motor impairment seen in most schizophrenic patients. Egashira et al. demonstrated a diminished function in the social interaction test, which is appropriate for measuring the socio-cognitive behavior of KO VI1aR mice of both sexes, but this was not observed after antagonist treatment (Bleickard et al, Psychopharmacology (Berl), 2009). , 202:711-18).

[0011] Two microsatellite polymorphisms associated with autism can be determined in the case of variants of the AVPRIA gene encoding the Vla receptor ( Kim et al., Mol Psychiatry 2002, 7:503-7; Yirmiya et al., Mol Psychiatry 2006, 11:488-94; Yang et al., Psychiatry Res, 2010, 178(1):199-201; Yang et al., Neurosci Lett 2010, 479(3):197-200 ). This also refers to a genetic connection that altered amygdala activation that could be detected in patients carrying two risk alleles in the VIaR gene. These modified receptors have been shown to be able to alter the amygdala activation threshold during the process of emotional facial recognition (Meyer-Lindenberg et al., Mol Psychiatry 2009, 14:968-75).

[0012] Preclinical data also support the efficacy of VlaR antagonists in autism. A widely used and accepted animal model of autism is to study the behavior of rats exposed to valproate (VPA) treatment in utero. The reduced social behavior of VPA treated animals can be reversed by the VIaR antagonist compound to the normal level. In a functional magnetic resonance imaging study, it was also found that decreased perfusion values were restored by the VlaR antagonist in different brain regions of animals prenatally treated with VPA. Decreased function of the cortex, inferior colliculus, hippocampus, and hypothalamus was increased by treatment with the VIaR antagonist, whereas in the ventral tegmentum, striatum, and superior colliculus, increased perfusion was normalized by the V1aR antagonist (Grundschober et al. al., poster presented at the Annual Meeting of the American College of Neuropsychopharmacology, 2014, Phoenix, USA). For this reason, VlaR antagonist compounds showing favorable penetration of the blood-brain barrier are expected to be advantageous.

[0013] Influencing VlaR with small molecule antagonists is a promising strategy for the treatment of various pathological conditions of the female sex organs (such as, but not limited to, dysmenorrhea, sexual dysfunction), long-term pathological conditions in blood pressure control (such as, but not limited to, hypertension and/or chronic heart failure), conditions resulting from inappropriate vasopressin secretion (such as, but not limited to, diabetes insipidus, renal failure, nephrotic syndrome, and cirrhosis). This can be considered as another promising strategy in the treatment of anxiety, depression, aggression, and central nervous system disorders where one of the symptoms and/or syndromes of the disease may be related to the last three diseases or show comorbidity with them. These include, but are not limited to, Autism Spectrum Disorder (Autism with Good Functioning, Asperger Syndrome, Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS), Autism Spectrum Disorder (ASD) and its various forms syndromes: fragile X syndrome, Prader-Willi syndrome, Rett syndrome, tuberous sclerosis), obsessive compulsive disorder (OCD), various forms of Down syndrome, and post-traumatic stress disorder (PTSD). VlaR antagonists are also suitable for the treatment of aggressive behavioral disorders and/or irritability (such as, but not limited to, patients with ASD, or suffering from Huntington's disease (HD) or various forms of schizophrenia), behavioral disorders of hyperactivity (such as, but not limited to, attention deficit hyperactivity disorder (ADHD)), cognitive disorders (such as, but not limited to, dementia, mild cognitive impairment (MCTLI), cognitive impairment associated with schizophrenia (CIAS) , and Alzheimer's disease), and other neuropsychiatric disorders (such as, but not limited to, schizophrenia and associated diseases).

[0014] Many patent applications deal with Vla receptor antagonists, for example, Otsuka describes benzoheterocyclic derivatives (WO 95/034540 Al, WO 2009/001968 Al, WO 2011/052519 Al), Astellas Pharma (Yamanouchi) describes derivatives of Condensed benzodiazepine and triazole ( WO 95/03305 A1 , WO 01/87855 A1 , WO 02/44179 AJ ), AbbVie describes oxindole derivatives ( WO 2006/072458 A2 , WO 2006/100082 A2 ), Bayer Pharma describes aryl- or heteroaryltriazole (WO 2017/191102 Al, WO 2017/191107 Al, WO

2017/191114 Al). Various benzoazulene core-containing derivatives (WO 2005/068466 A1, WO 2006/021213 A2, WO 2006/021882 A1, WO 2011/114109 A1, WO 2011/128265 A1, WO 2011/141396 A1, WO 2014/127350 A1), spiroindolinone and indolylcarbonyl derivatives (WO 97/15556 A1, WO 2007/009906 A1, WO 2007/014851 A2) are also described as V1la receptor antagonists.

[0015] The first clinical developments considered the Vla receptor as a peripheral target, the low penetration in the brain was thus beneficial in the development of compounds. Such was Sanofi's indoline core compound, relcovaptan (SR-49059, WO 93/03013 Al), which was developed up to the Phase 2 clinical trial. Among the indications studied were premature birth, pelvic pain observed during menstruation, dysmenorrhea (Brouard et al., Br J Obstetr Gynaecol 2000, 107:614-9), heart failure, hypertension, and coronary spasm, but it was also tested as an antineoplastic agent in small cell lung carcinoma until the last experiment clinical trial was discontinued in 2003 (Serradeil-Le Gal et al, Prog Brain Res 2002, 139:197-210; AdisInsight: Relcovaptan - Information last updated: October 3, 2006 http://adisinsight.springer.com/drugs /800004942). Relcovaptan has been in clinical development since 1993 and is used most frequently as an in vitro tool in VlaR research ( Tahara et al., Br J Pharmacol 2000, 129:131-9 ).

[0016] Pfizer has studied its triazole derivative PF 00738245 (WO 2005/063754 Al) and triazolobenzodiazepine core compound PF-184563 (WO 2004/074291 Al) in preclinical development for dysmenorrhea, and based on measured data, these are efficient VlaR antagonists (Russell et al., Eur. J Pharmacol, 2011, 67002): 347-355 ; Johnson et al., Bioorg Med Chem Lett 2011, 21:5684-7), but its development has ended.

[0017] By examining the effects exerted on the central nervous system, the treatment of depression and anxiety has also been elevated as a new therapeutic area. The Johnson & Johnson compound JNJ-17308616 core spirobenzazepine was one of the first VlaR antagonist compounds acting on the central nervous system (Bleickard et al., Psychopharmacology (Berl.), 2009, 202:711-18; WO 02/02531 Al ) that have demonstrated efficacy in a variety of different animal models used for anxiety research: significantly reduced anxiety behavior in the elevated positive maze test, the marble burying test, and ultrasonic vocalization induced by the separation of rat pups. Although it proved to be effective in influencing the elevated O-maze response and the conditioned licking response, due to its low metabolic stability measured in rodents, its effectiveness was not good and was measurable only at high doses, and thus was difficult to test. .

[0018] Azevan's VlaR antagonist azetidone derivatives, SRX246 and SRX251 (also known as API246 or APLI251, WO 03/031407 A2) have also reached the clinical trial stage. Clinical trials of SRX246 are also currently underway for the treatment of aggression, and intermittent explosive disorder and irritability in Huntington's disease and post-traumatic stress disorder, as well as in human behavioral models of anxiety and fear (AdisInsight: SRX 246 - Information last updated: February 16, 2017 http://adisinsight.springer.com/drugs/800023656). Clinical trial was conducted with SRX251 to treat dysmenorrhea, but both Phase 1 studies were discontinued in 2016, and similarly for SRX246, it was also investigated for preclinical developmental aggression (AdisInsight: SRX 251 - Latest Information Update: 04 Nov 2017 http://adisinsight.springer.com/drugs/800025117). SRX-246 and SRX-251 are active at the human Vla receptor and in rats both compounds were detectable in the brain at approximately 100-fold the effective concentrations in the binding test (Guillon et al., Bivorg Med Chem 2007, 15:2054- 80; Fabio et al., 7 Pharm Sci 2013, 102(6):2033-43 ).

[0019] The Vantia V1aR antagonist compound, Pyrazolobenzodiazepine core VA 111913 (WO 2010/097576 Al; AdisInsight: VA 111913 - Information last updated: August 25, 2015 http://adisinsight.springer.com/drugs /800028777) was tested in a Phase 2 clinical trial for the treatment of dysmenorrhea, but there is no information about its development since 2015.

[0020] Otsuka's VIlaR antagonist, the quinolinone derivative OPC 21268 (EP0382185A2; AdisInsight: OPC 21268 — Information last updated: 06 Oct. 2006 http://adisinsight.springer.com/drugs/800000284) was tested for indication of gastric mucosal damage in the preclinical phase, whereas in Phase 2 clinical trials it was tested for heart failure and hypertension, but there is no information about its development since 2015 (Yamamura et al., Science 1991, 252: 572; Serradeil-Le Gal et al., J Clin Invest 1993, 92(1):224 ).

[0021] By examining the brainstem in post-mortem human samples, selective localization of Vla receptors unrelated to oxytocin receptors can be detected in the nucleus prepositus, which plays a role in gaze point stabilization (Freeman et al. , Soc Neurosci 2017, 12 (2): 113-123 ). A fundamental skill required for human social behavior is the recognition and eye tracking of biologically relevant information (Klin et al., Nature 2009, 459:257-63, Simion et al, PNAS 2008, 105(2):809-13) . The most active VlaR researcher Hoffmann-La Roche achieved the Phase 1 study with its indole derivative ROS028442 (RG-7713; WO 2007/006688 Al), where the positive effect on gaze pattern orientation could be detected in humans (Umbricht et al., Neuropsychopharmacology 2017, 42

(9):1914-1923; AdisInsight: RG 7713 - Information last updated: November 5, 2015 http://adisinsight.springer.com/drugs/800043668). Phase 2 clinical trials for treating autism are currently ongoing with triazolobenzodiazepine core balovaptan (RG-7314, ROS285119; WO 2010/060836 Al; AdisInsight: RG 7314 - Last information update: 10 Sep. 2017 http:/ /adisinsight.springer.com/drugs/ 800035102).

[0022] Despite numerous VIaR antagonist compounds and clinical studies, an unmet medical need still persists to develop a VIaR antagonist that is appropriate for the treatment and/or prophylaxis of various pathological conditions of the female sex organs, conditions in long term. permanence of blood pressure control, conditions resulting from inappropriate vasopressin secretion, anxiety, depression, aggression, central nervous system disorders where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavior disorders and/or irritability, hyperactive behavioral disorders, cognitive disorders or other neuropsychiatric disorders.

SUMMARY OF THE INVENTION

[0023] Applicants' objective was to synthesize new structured Vla receptor antagonists whose physical-chemical (e.g. kinetic or thermodynamic solubility, ionization, lipophilicity or permeability) or pharmaceutical (e.g. metabolic stability, CYP- 450) provide favorable D-bioavailability, ADME (absorption, distribution, metabolism, excretion), membrane penetration or blood-brain barrier penetration.

[0024] Surprisingly, such new derivatives of 5,6-dihydro-4H-

[1,2 4]triazolo[4,3-a][1]benzazepine of general formula (1) were prepared that show a profile of V1la receptor antagonistic activity.

[0025] The present invention relates to compounds of general formula (1) a, Dx

A no. wherein ring A is a cycloalkyl or heterocyclyl group; Y is -O-, -C(O)-, -CH7 -, -NH-, -C14 alkyl-N(R')- or bond if ring B is present; or -N(Cisalkyl)., C(OO)OCi,alkyl,Cyalkyl optionally substituted with halogen, C1,4alkoxy group or halogen if ring B is not present; ring B is an optionally substituted heteroaryl, aryl or heterocyclyl group; or B-Y-A- together represents 3H-spiro[2-benzofuran-1,4-piperidin-1*-11]; or d, X, Sl zN zN YO group. or group “YOU.. or group x.

R' is a hydrogen, halogen, C1, alkyl, C1,4 alkoxy, CF3 or CN; R° is a hydrogen or C ,4 alkyl group; R? is an NRR', OR group or halogen; or Rº and R? together they represent -O-(CH₂)1n-O-, oxo group or =N-OH; Rº and Rº is independently a hydrogen; C1,alkyl optionally substituted with OH group, halogen, cycloalkyl, optionally substituted aryl or NRºRº; Cy!; COLOR"; S(O0:)R"° or C2.1alkynyl group;

or R° and R6 taken together with the N to which they are attached form a heterocycle;

Rº is a hydrogen; C 14 alkyl optionally substituted with OH, halogen, Cy', C 1 4 alkoxy, C 1 4 alkoxy-S(OO) group or NRUR 1' group; C(O)R"3; SI(CH2 ),5-t-butyl or C1,alkynyl group;

R' is a C1,4 alkyl optionally substituted with OH, CN, halogen, Cy? or NRUR"?; C1,alkoxy, Cr,alkenyl, Cy? or N(C1,1 alkyl);

Rº and Rº is independently a hydrogen, group C, ,alkyl or C(O)OR?!;

R'° is a C1,4alkyl, OH or NRYR group";

R" and R1' is independently a hydrogen or C.1 alkyl group;

or R"' and R*' taken together with the N to which they are attached form an optionally substituted heterocycle;

R"? is a C1,4 alkyl optionally substituted with CN or NR1R" group; Cy? or NR1R"! group;

R!* º R! is independently a hydrogen or Cr group. 1alkyl;

R'!º º RU is independently a hydrogen, group Cr. 4alkyl, or optionally substituted aryl;

or R!º and Rº taken together with the N to which they are attached form a heterocycle;

R'º and R? is a hydrogen or C₁₋₆alkyl group;

R"" and R* is independently a hydrogen or Cr.aalkyl group;

Cy! is an optionally substituted cycloalkyl, heterocyclyl or heteroaryl group; Cy is an optionally substituted aryl or cycloalkyl group; Cy? is an optionally substituted aryl, cycloalkyl, heterocyclyl or heteroaryl group; X is a C, ,alkyl, aryl or heteroaryl group; Z is a C1 alkyl group; m2,3,40u5 and/or salts thereof and/or geometric isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active metabolites thereof and/or prodrugs thereof and/or solvates thereof and/or hydrates thereof and/or polymorphs thereof.

[0026] The present invention also relates to pharmaceutical compositions containing the compound of general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate of the same and/or diastereomer of the same and/or prodrug of the same and/or solvate of the same and/or hydrate of the same and/or polymorph of the same as active substances.

[0027] Furthermore, the present invention also relates to the preparation of the compound of general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate of the same and/or diastereomer of the same and/or prodrug of the same and/or solvate of the same and/or hydrate of the same and/or polymorph of the same, to the intermediates of the preparation process and the preparation of chemical and pharmaceutical products of pharmaceutical compositions containing the compounds.

[0028] The invention also relates to a method of treating a mammal, including humans, suffering from a central and/or

14/323, where modulation, preferably antagonism, of the V1la receptor may have therapeutic benefits wherein the compound of formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof or a therapeutically effective amount thereof in a composition is administered.

[0029] The invention also relates to the use of the compound of general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and /or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof for the manufacture of a medicament for the treatment and/or prophylaxis of an associated disease or condition with the function of Vla receiver.

DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention relates to Vla receptor modulators, in particular Vla receptor antagonists. It is a further object of the invention to provide selective β-receptor inhibitor compounds because selectivity is less likely to cause undesirable side effects. Another aspect of the invention is to provide compounds with favorable physicochemical properties, as favorable physicochemical properties are expected to result in beneficial bioavailability, ADME (absorption, distribution, metabolism, excretion), membrane penetration or blood-brain barrier penetration. of the compounds.

[0031] The compounds of general formula (1) of the present invention are thus Vla receptor antagonists which are therapeutic agents with central and/or peripheral action in the treatment and/or prophylaxis of various pathological conditions of the female sexual organs, conditions long-term blood pressure control, conditions resulting from inappropriate vasopressin secretion, anxiety, depression, aggression, central nervous system disorders where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autism spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavior disorders and/or irritability, hyperactive behavioral disorders, cognitive disorders or other neuropsychiatric disorders.

[0032] The present invention relates to compounds of general formula (1) & Nx

NA R? wherein ring A is a cycloalkyl or heterocyclyl group; Y is -O-, -C(O)-, -CH7-, -NH-, -C1-4alkyl-N(R'9)- or bond if ring B is present; or -N(C14 alkyl), C(O)OCr,alkyl, C14 alkyl optionally substituted with halogen, C14 alkoxy group or halogen if ring B is not present; ring B is an optionally substituted heteroaryl, aryl or heterocyclyl group; or BYA- together represents 3H-spiro[2-benzofuran-1,4'-piperidin-1"-yl]; or X, do, DA 2 7 "O." group or "O." group or x.R' group is a hydrogen, halogen, C1,alkyl, C14alkoxy, CF3 or

16 /323 CN;

Rº is a hydrogen or C1-4 alkyl group;

Rô is a NRºRó, OR” or halogen group;

or R? and R? together they represent -O-(CH 2 )n-O-, OxO or =N-OH group;

Rº and Ró is independently a hydrogen; C1,alkyl optionally substituted with OH group, halogen, cycloalkyl, optionally substituted aryl or NRºRº; Cy!; COLOR'; S(O»)R"* or Cz.1alkynyl group;

or R? and R6 taken together with the N to which they are attached form a heterocycle;

R$ is a hydrogen; C1,4alkyl optionally substituted with OH group, halogen, Cy2, C1,alkoxy, C14alkoxy-S(OO); or NRUR!?; C(O)R"?; Si(CH;3 ), ;-t-butyl or Cy,alkynyl group;

R' is a C1,4 alkyl optionally substituted with OH, CN, halogen, Cy? or NRUR"?; C1,4alkoxy, Ca1,Cy, or N(C1,aalkyl)o group;

Rº and Rº is independently a hydrogen, C group, 1alkyl or C(O)OR?';

R'º is a Cr4 alkyl, OH or NR1 R'S group;

R!' and R*? is independently a hydrogen or C1 group. 1alkyl;

or R"' and R1' taken together with the N to which they are attached form an optionally substituted heterocycle;

R" is a C1,alkyl optionally substituted with CN or NR/ºR group; Cy' or NR'R group";

R'* º RU is independently a hydrogen or Cr group. alkyl;

R'º º RU is independently a hydrogen, group Cx.

1alkyl, or optionally substituted aryl; or R'* and Rº taken together with the N to which they are attached form a heterocycle; R'?* and Rºº is a hydrogen or C₁₋,alkyl group; R" and R" is independently a hydrogen or C1 alkyl group; Cy' is an optionally substituted cycloalkyl, heterocyclyl or heteroaryl group; Cy is an optionally substituted aryl or cycloalkyl group; Cy' is an aryl, cycloalkyl, heterocyclyl or optionally substituted heteroaryl; X is a C, ,alkyl, aryl or heteroaryl group; Z is a C, ,alkyl group; m2,3,40u5 and/or salts thereof and/or geometric isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active metabolites thereof and/or prodrugs thereof and/or solvates thereof and/or hydrates thereof and/or polymorphs of the same.

[0033] The definition of the general terms used here, whether or not the terms in question are presented individually or in combination with other groups, is given below.

[0034] The term "cycloalkyl group" refers alone or in combination with other groups to saturated or unsaturated, preferably saturated 3 to 8 membered, preferably 3 to 6 membered, carbocyclic groups. Examples include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In ring A, the term "cycloalkyl group" preferably refers to a saturated or unsaturated, preferably saturated, 4- to 6-membered carbocyclic group. Examples include cyclobutyl, cyclopentyl or cyclohexyl, more preferably cyclobutyl or cyclohexyl. The cyclohexyl group is particularly preferred. The term "substituted cycloalkyl group" preferably refers to a cycloalkyl group having geminal halogen substitution.

[0035] The term "aryl group" refers alone or in combination with other groups to a 6 to 14 membered, preferably 6 to 10 membered, carbocyclic aromatic moiety comprising at least one aromatic ring or a condensed ring system containing at least an aromatic ring. Examples include, but are not limited to, phenyl, benzyl, naphthyl, biphenyl, anthryl, azulenyl, or indanyl. The phenyl group is particularly preferred.

[0036] The term "heterocyclyl group" refers alone or in combination with other monocyclic and bicyclic, saturated or unsaturated, preferably saturated, 3- to 8-membered, preferably 4- to 7-membered, fused ring-cycled and/or bridged bonds containing 1, 2 or 3 heteroatoms selected from O, S or N. Examples include, but are not limited to, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, piperidine, pyrrolidine, morpholine, piperazine, 1,3-oxazolidine, 1 ,3-thiazolidine, thiomorpholine 1,1-dioxide, azepane, 1-azabicyclo[2,2,2]joctane and the like. Preferably — pyrrolidinyl, — piperidinyl, — piperazinyl — or 1-azabicyclo[2,2,2]oct-3-yl. More preferably, piperidinyl or piperazinyl.

[0037] When ring A is heterocyclyl, then heterocyclyl preferably refers to a 4- to 7-membered saturated heterocyclyl group containing 1 or 2 N, in which ring A is attached via a nitrogen in the ring to Y or the triazole ring of the nucleus. 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine. Examples include, but are not limited to, azetidinyl, 1,3-diazetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, azepanyl, 1,3- or 1,4-diazepanyl. Preferably azetidinil, pyrrolidinil,

piperidinyl or piperazinyl. Piperidinyl is particularly preferred.

[0038] In the case of Cy' or Cy, the heterocycle preferably refers to a 4- to 7-membered saturated heterocyclyl group containing | O, more preferably oxetane or tetrahydropyran.

[0039] When "Rº and Ró taken together with the N to which they are attached form a heterocycle", the heterocycle preferably refers to a saturated 4- to 7-membered ring containing 1, 2 or 3 heteroatoms selected from O, S or N, more preferably pyrrolidine, 3-oxazolidine, 1,3-thiazolidine, piperidine, piperazine, morpholinyl or thiomorpholine-1,1-dioxide.

[0040] When “R!! and RI", or "R1º and R'7 taken together with the N to which they are attached form a heterocycle", the heterocycle is preferably selected from the group comprising morpholin-4-yl, 4-methylpiperazin-1-yl , pyrrolidinyl, piperidinyl, piperazinyl, 1,3-oxazolidine, 1,3-thiazolidine or thiomorpholine-1,1-dioxide.

[0041] The term "heteroaryl group" refers alone or in combination with other groups to a cyclic aromatic group containing a single 5- to 6-membered ring containing 1, 2 or 3 heteroatoms in which group at least one heterocyclic ring is aromatic . "6-membered monoheteroaryl" refers to a monocyclic aromatic group that is a single 6-membered ring containing 1, 2, or 3 heteroatoms selected from O, S, or N. Examples include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl and the like. Preferred single 6-membered monoheteroaryl groups contain | or 2 N. The preferred 6-membered ring is pyridinyl, more preferably pyridin-2-yl and pyridin-3-yl. Pyridin-2-yl is particularly preferred. The term "5-membered monoheteroaryl" refers to a monocyclic aromatic group that is a single 5-membered ring containing 1, 2, or 3 heteroatoms selected from O, S, or N. Preferred 5-membered monoheteroaryl groups contain 2 Ne 10.2 NelS 2N INoulSoulNeloO. Examples include, but are not limited to, thiophenyl, furanyl, pyrrolyl, imidazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, 1H-pyrazolyl, triazolyl, and the like. A preferred 5-membered ring is isoxazol-3-yl and 1,3,4-oxadiazol-5-yl.

[0042] In the case of Cy!, heteroaryl preferably refers to a 6-membered monoheteroaryl group containing 1 or 2 N, more preferably pyridine, pyrimidine or pyrazine.

[0043] When ring B is an optionally substituted heteroaryl group, the heteroaryl group is preferably 3-chloropyridin-2-yl, 3-methylpyridin-2-yl or 5-methylisoxazol-3-yl.

[0044] The term “bond” refers to a single bond, in which a pair of electrons is shared between two atoms.

[0045] The term "Cyaalkyl group" refers alone or in combination with other groups to a straight or branched, single or multiple, branched hydrocarbon radical, and consists of 1 to 4 carbon atoms. Examples include, but are not limited to, methyl, ethyl, propyl, i-propyl (isopropyl), n-butyl, 2-butyl (sec-butyl) or r-butyl (tert-butyl) group. Preferred alkyl groups are those consisting of of 1 to 3 carbon atoms More preferred are methyl, ethyl and isopropyl groups The methyl group is particularly preferred.

[0046] The term "Ci,alkenyl group" refers alone or in combination with other groups to a straight or branched, single or multiple, branched hydrocarbon radical having a double bond and consisting of 2 to 4 carbon atoms. Examples include, but are not limited to, vinyl, propen-1-yl, propen-2-yl, butene-1-yl or butene-3-yl. Preferred alkenyl groups are those consisting of 2 to 3 carbon atoms. The vinyl group is particularly preferred.

[0047] The term "Ci,alkynyl group" refers alone or in combination with other groups to a hydrocarbon radical having a triple bond and consisting of 2 to 4 carbon atoms. Examples include, but are not limited to, ethynyl, propynyl, propargyl, 1-butynyl, 2-butynyl and the like. Preferred alkynyl groups are those consisting of three carbon atoms. More preferred is the propargyl group.

[0048] The term "Cyalkoxy group" refers alone or in combination with other groups to the O-C1,alkyl group, wherein the C1. 1alkyl is as defined above. Examples include, but are not limited to, methoxy, ethoxy, propoxy, r-butoxy. Preferred alkoxy groups are methoxy, propoxy or t-butoxy. Particularly preferred are methoxy and t-butoxy.

[0049] The term “Boc” refers alone or in combination with other groups to the t-butoxycarbonyl group

[0050] The term "halogen" refers alone or in combination with other groups to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably chlorine or bromine. Chlorine is particularly preferred.

[0051] The term "optionally substituted" at any atom of the relevant group refers to substitution by one or more C1,alkyl, C1,alkoxy, oxo or halogen groups. Here, "one or more" means from one to the greatest possible number of substitutions, that is, from substitution of one hydrogen to substitution of all hydrogens. One, two or three substituents on a given atom are preferred. Even more preferred are one or two, or a substitution. A substitution for a substituted aryl or heteroaryl group is particularly preferred. The expression “C,. 1alkyl optionally substituted with halogen" preferably refers to a C1,alkyl group having one, two or three halogen substituents on any atom of the C1,alkyl group, more preferably to a methyl group having three halogen substituents. The CF3 group is particularly preferred.

[0052] The term "salt" refers to pharmaceutically acceptable and/or pharmaceutically unacceptable salts. Pharmaceutically acceptable salt refers to conventional acid addition and base addition salts which preserve the efficacy and biological properties of compounds of general formula (1) and which can be formed with appropriate non-toxic organic or inorganic acids or organic bases or inorganic. Examples of acid addition salts include salts derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and perchloric acid and derivatives of various acids. organic acids such as, but not limited to, acetic acid, propionic acid, benzoic acid, glycolic acid, phenylacetic acid, salicylic acid, malonic acid, maleic acid, oleic acid, pamoic acid, palmitic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid, succinic acid, citric acid, malic acid, lactic acid, glutamic acid, fumaric acid and the like. Examples of base addition salts are salts derived from hydroxides of ammonium, potassium, sodium and quaternary ammonium, such as tetramethylammonium hydroxide. These salts often exhibit more favorable solubility properties than the compounds used for their preparation and are therefore more suitable for use in the preparation of, for example, liquid or emulsion formulations. Pharmaceutically unacceptable salts may be preferred for the purification and isolation of compounds of general formula (1) and therefore also fall within the scope of the invention.

[0053] The term "prodrug" refers to derivatives of compounds of general formula (1) according to the invention which do not themselves have a therapeutic effect, but contain such groups which, after chemical or metabolic degradation in (biotransformation), become “biologically active metabolites” and are responsible for the therapeutic effect. Such decomposition groups associated with the compounds of general formula (1) of the present invention, in particular those suitable for prodrugs, are known in the art and can also be applied to the compounds of the present invention (Rautio et al., Nat Rev drug Discov 2008, 7:255-270).

[0054] The compounds of general formula (1) can exist in various geometric isomeric forms. Furthermore, some compounds of general formula (1) may contain one or more asymmetric centers, thus they exist in the form of stereoisomers and diastereomers. All these compounds, such as cis isomers, trans isomers, diastereomeric mixtures, racemates, non-racemic mixtures of enantiomers, substantially pure and pure enantiomers are also within the scope of the invention. Substantially pure enantiomers contain up to 5% by weight, preferably 2% by weight, most preferably 1% by weight, of the corresponding opposite enantiomer.

[0055] Optical isomers can be prepared by resolving the racemic mixtures by known methods, for example using an optically active acid or base to form diastereoisomeric salts or forming covalent diastereomers. Suitable acids include, for example, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Diastereoisomeric mixtures can be separated into individual diastereomers based on their physical and/or chemical differences, by methods known to those skilled in the art, such as chromatography or fractional crystallization. Subsequently, the optically active bases or acids are released from the separated diastereoisomeric salts. Various optical isomer separation methods include chiral chromatography (eg chiral HPLC columns) optionally used by derivatization with the aim of maximizing enantiomer separation. Suitable chiral HPLC columns are Diacel columns, such as CHIRALPAK or CHIRALCEL columns, which can be routinely chosen as desired. Where applicable, enzymatic separations performed by derivatization can also be used. Optically active compounds of general formula (1) can also be prepared using starting materials

24 /323 optically active using chiral synthesis without racemization reaction conditions.

[0056] The absolute configuration of chiral compounds was determined by the VCD method (vibrational circular dichroism spectroscopy) described in the literature (Freedman et al., Chirality 2003, 15(9):743-58; Stefens et al, Chirality 2008, 20 :643-663) and/or by 1 H NMR spectroscopic testing of the diastereomeric pair of compounds synthesized from chiral compounds ( Seco et al., J Org Chem 1999, 64:4669-4675 ; Seco et al., Tetrahedron Asymmetry 2001, 12:2915-2925; Latypov et al., JL Am.Chem.Soc. 1998, 120, 4741-4751).

[0057] The compounds of general formula (1) can exist in various polymorphic forms. As is known in the art, polymorphism is the ability of a compound to crystallize in more than one crystalline form, i.e. in polymorphic form. The polymorphic forms of a particular compound can be defined by identical chemical formula or composition and differ in their chemical structure, like the crystal structures of two different chemical compounds.

[0058] The compounds of general formula (1) and salts thereof may also be present as solvates or hydrates, which are also within the scope of the invention. The term "solvate" refers to non-covalent combinations of solvent and solute. The term "hydrate" refers to non-covalent combinations of water and solute.

[0059] The present invention further relates to pharmaceutical compositions containing the compound of general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof.

[0060] The present invention also relates to the chemical or pharmaceutical preparation of pharmaceutical compositions containing the compound of general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof same and/or racemate thereof and/or diastereomer thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof.

[0061] The pharmaceutical compositions of the present invention can be formulated into various pharmaceutical formulations, such as, but not limited to, solid oral dosage forms such as tablets (e.g., buccal, sublingual, effervescent, chewable, orally dispersible), capsules, pills, mints, orally dispersible films, granules, powders; liquid formulations such as solutions, emulsions, suspensions, syrups, elixirs, drops; parenteral dosage forms, such as intravenous injections, intramuscular injections, subcutaneous injections; other forms of medicine such as eye drops, semi-solid ophthalmic preparations, semi-solid dermal preparations (such as ointments, creams, pastes), transdermal therapeutic systems, suppositories, rectal capsules, rectal solutions, emulsions and suspensions, etc.

[0062] An embodiment of the invention relates to pharmaceutical compositions for pediatric use, such as, among others, solutions, syrups, elixirs, suspensions, powders for the preparation of suspensions, dispersible or effervescent tablets, chewable tablets, orodispersible tablets, tablets or coated tablets, orally foaming powders or granules, capsules.

[0063] The pharmaceutical compositions of the present invention can be prepared by methods known per se, such as mixing, dissolving, emulsifying, suspending, microencapsulation, lyophilization, extrusion and spheronization, lamination, film coating, granulation, encapsulation, tableting. or conventional pressing.

[0064] The pharmaceutical compositions of the present invention can

26 /323 be formulated in the usual manner using one or more physiologically acceptable excipients, including binders, which promote the incorporation of the active substance into pharmaceutically acceptable dosage forms. The appropriate formulation depends on the chosen mode of administration. Any of the techniques and excipients well known in the art can be used.

[0065] The excipients applicable in the preparation may be selected from the following categories, such as, but not limited to, tablet and capsule fillers, tablet and capsule binders, modified drug release agents, disintegrants, glidants, lubricants, sweeteners, taste masking agents, flavors, coating materials, surfactants, stabilizers, preservatives or antioxidants, buffering agents, complexing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, lyophilization excipients, microencapsulation agents, ointment materials , penetration enhancers, solubilizers, solvents, suppository materials, suspending agents. Suitable pharmaceutical excipients may be, for example: starch, microcrystalline cellulose, talc, glucose, lactose, gelatin, silica, talc, magnesium stearate, sodium stearate, glycerol monostearate, cellulose derivatives, sodium chloride, glycerol, propylene glycol , water, ethanol and the like.

[0066] Another embodiment of the present invention relates to the use of special binders that can improve the solubility, dissolution, penetration, absorption or bioavailability of the active substance(s), such as, but not limited to, polymers hydrophilic, hot melt extrusion excipients, surfactants, buffering agents, complexing agents, emulsifying agents, -lyophilizing excipients, disintegrants, microencapsulating agents, penetration enhancers, solubilizers, co-solvents, suspending agents.

[0067] The excipients described above and the various methods of preparation are representative examples only. Other materials and process techniques known in the art may also be used.

[0068] The terms "disease or condition associated with V1a receptor function" or "disease or condition associated with central and/or peripheral modulation, preferably antagonization of the V1a receptor" refer to a disease or condition selected from among the group consisting of various pathological conditions of the female sexual organs, conditions in long-term control of blood pressure, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autism spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavior disorders and/or irritability, hyperactivity, cognitive disorders or other neuropsychiatric disorders.

[0069] The various pathological conditions of the female sex organs include, but are not limited to, dysmenorrhea (primary and/or secondary) or sexual dysfunction.

[0070] Long-term blood pressure control conditions include, but are not limited to, hypertension and/or chronic heart failure.

[0071] Conditions resulting from inappropriate vasopressin secretion include, but are not limited to, diabetes insipidus, renal failure, nephrotic syndrome, or cirrhosis.

[0072] Disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them, include, but are not

28/323 limited to, Autism Spectrum Disorder (Autism with Good Functioning, Asperger Syndrome, Pervasive Developmental Disorder - Not Otherwise Specified (PDD-NOS), Autism Spectrum Disorder (ASD) and its various forms syndromes: fragile X syndrome, Prader-Willi syndrome, Rett syndrome, tuberous sclerosis), obsessive compulsive disorder (OCD), various forms of Down syndrome and post-traumatic stress disorder (PTSD).

[0073] Aggressive behavioral disorders and/or irritability include, but are not limited to, ASD, Huntington's disease, or different forms of schizophrenia.

[0074] Behavioral disorders of hyperactivity include, but are not limited to, attention deficit hyperactivity disorder.

[0075] Cognitive disorders include, but are not limited to, dementia, mild cognitive disorders, cognitive impairment associated with schizophrenia or Alzheimer's disease.

[0076] The other neuropsychiatric disorders include, but are not limited to, schizophrenia and associated illnesses.

[0077] In one embodiment, the disease or condition associated with V1a receptor function or the disease or condition associated with central and/or peripheral modulation, preferably Vla receptor antagonization refers to autism spectrum disorder.

[0078] The present invention relates to a method of treating and/or preventing a disease or condition associated with V1la receptor function, comprising administering to a subject in need of treatment — and/or prophylaxis, preferably a mammal, more preferably a human, of a therapeutically effective amount of a compound of general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof same and/or diastereomer of the same and/or pro-

29/323 drug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof alone or with at least one pharmaceutically acceptable excipient in the form of a pharmaceutical formulation.

[0079] The present invention relates to a method for treating an individual, preferably a mammal, more preferably a human, suffering from a disease or condition selected from the group consisting of various pathological conditions of the female sexual organs, conditions long-term blood pressure control, conditions resulting from inappropriate vasopressin secretion, anxiety, depression, aggression, central nervous system disorders where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autism spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavior disorders and/or irritability, hyperactive behavioral disorders, cognitive or other neuropsychiatric disorders, or a combination of these illnesses. This method of treatment comprises administering to a subject in need of such treatment, preferably a mammal, more preferably a human, the therapeutically effective amount of the compound of formula (1) and/or salt thereof and/or geometric isomer of the same. the same and/or stereoisomer of the same and/or enantiomer of the same and/or racemate of the same and/or diastereomer of the same and/or prodrug of the same and/or solvate of the same and/or hydrate of the same and/or polymorph of the same same. The method of treatment may include administering to a subject in need of such treatment, preferably a mammal, more preferably a human, a therapeutically effective amount of a pharmaceutical composition comprising the compound of formula (1) and/or salt of the same. same and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate of the same and/or polymorph of the same.

[0080] The present invention relates to the use of the compound of general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof for the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition associated with Vla receptor function.

[0081] The term “treatment” refers to the alleviation of a specific pathological condition, the elimination or reduction of one or more of the symptoms of the condition, the slowing or elimination of the progression of the disease state, and the prevention or delay of the recurrence of the condition. pathological condition of a patient or individual already suffering from or diagnosed with the disease. The "prevention" (or prophylaxis or delay of the occurrence of the disease) is typically accomplished by administering the drug in the same or similar manner as if it were administered to a patient with an already developed disease or condition.

[0082] The term “therapeutically effective amount” refers to the amount of active substance that results in the treatment, cure, prevention or amelioration of the disease or pathological condition or side effect and reduces the progression of the disease or pathological condition compared to the individual correspondent who did not receive this amount. The term also includes amounts effective to enhance normal physiological functioning. For use in therapy, the compound of general formula (1) and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug of the same and/or solvate thereof and/or hydrate thereof and/or polymorph thereof as well as any pharmaceutically acceptable salt thereof may be administered in a therapeutically effective amount as a raw chemical. Furthermore, the active substance can be made available as a pharmaceutical formulation. The exact therapeutically effective amount of the compound of general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof depends on a number of factors including, but not limited to, age and body weight of the subject (patient) treated, the precise type of disease requiring treatment and its severity, the nature of the medicinal product and the route of administration.

[0083] The term “mammal” refers to any member of the class “Mammalia”, including, but not limited to, humans.

[0084] The present invention also relates to pharmaceutical compositions comprising the compound of general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof suitable for the treatment of a disease or condition associated with central modulation and /or peripheral, preferably Vla receptor antagonization.

[0085] The compound of the invention may also be used in combination with one or more of the compounds of the invention or with one or more other active substances (e.g. psycholeptics, psychoanaleptics, antihypertensives, spasmolytics, antiepileptics or other agents) in a mammal, including but not limited to humans, suffering from a central and/or peripheral disease, where central and/or peripheral modulation, preferably Vla receptor antagonization, has therapeutic benefits.

[0086] Psycholeptics include, but are not limited to, antipsychotics,

anxiolytics, and hypnotic or narcotic sedatives.

[0087] Antipsychotics include, but are not limited to, typical and atypical antipsychotics such as phenothiazines with aliphatic side chains (chlorpromazine, promazine, levomepromazine, acepromazine, trifluproazine, cyamemazine, chlorproetazine, protypendyl), piperazine-derived phenothiazines (dixirazine, fluphenazine). , perazine, perphenazine, prochlorperazine, thiopropazate, trifluoperazine, acetophenazine, thioproperazine, butaperazine, perazine), piperidine-derived phenothiazines (periciazine, thioridazine, mesoridazine, — pipothiazine), thioxanthenes (chlorprothixene, clopenthixol, flupentixol, thiothixene, zuclopentixol), derivatives of zuclopentixol butyrophenone (haloperidol, triflupidol, melperone, moperone, pipamperone, bromperidol, benperidol, droperidol, thymiperone, fluanisone), diphenylbutylpiperidine derivatives (fluspirilene, penfluridol, pimozide), diazepine, oxazepine or thiazepine derivatives (clozapine, olanzapine, clothiapine, quetiapine, loxapine, azenapine), indole derivatives (sertindole, ziprasidone, lurazidone, molindone, oxipertine), benzamide derivatives (sulpiride, sultroppride, tiapride, remoxipride, amisulpride, veralipride, nemonapride, verasulpiride) or other agents (risperidone, aripiprazole, caripraziney Dbrexpiprazole, metoclopramide, mosapramine, — loperidone, paliperidone, amoxapinay amperoside, perospirone, carpipramine, clocapramine, tetrabenazine, lithium).

[0088] Anxiolytics — include, but are not limited to, benzodiazepines (diazepam, chlorodiazepoxide, medazepam, oxazepam, potassium chlorazepate, lorazepam, adinazolam, bromazepam, clobazam, cetazolam, prazepam, alprazolam, halazepam, pinazepam, camazepam, nordazepam, fludiazepam , ethyl loflazepate, etizolam, clothiazepam, coxazolam, tofizopam), diphenylmethane derivatives (hydroxyzine, captodiam), carbamates — (meprobamate, emylcamate, mebutamate), dibenzobicyclooctadiene derivatives (benzoquinone), azaspirododiones (buspirone), others agents (mefenoxalone, gedocarnil, y etifoxinay, fabomotizol,

33 /323 trimethosine), derivatives acting by increasing GABA-mediated inhibition, or compounds acting on a serotonin receptor, and other GABAergic agents (such as GABA,s 05 NAMs, e.g. basmisanil, GABAa, 05 PAM;s, e.g. example RG7816).

[0089] Sedative or narcotic hypnotics include, but are not limited to, barbiturates (pentobarbital, amobarbital, butobarbital, barbital, aprobarbital, secobarbital, talbutal, vinylbital, vinbarbital, cyclobarbital, heptabarbital, reposal, methohexitol, hexobarbital, thiopental, thalobarbital, alobarbital , proxybarbital), aldehydes (chloral hydrate, chloralodol, acetylglycinamide chloral hydrate, dichloralphenazone, paraldehyde), benzodiazepines (flurazepam, nitrazepam, flunitrazepam, estazolam, triazolam, lormetazepam, temazepam, midazolam, brotizolam, quazepam, loprazolam, doxefazepam, cinolazepam), derivatives of piperidindione (glutethimiday, metyprilon, pyrityldione), benzodiazepine derivatives of cyclopyrrolone (zopiclone, zolpidem, zaleplon, eszopiclone), melatonin receptor agonists (melatonin, ramelteon) or other hypnotics and sedatives (methaqualone, clomethiazole, bromisoval, carbromal, scopolamine, propiomazine , triclophos, etchlorvynol, — Valerianaee — Radix, —hexapropimati, —“br omets, apronal, valnoctamide, methylpentinol, niaprazine, dexmedetomidine).

[0090] Psychoanaleptics include, but are not limited to, psychostimulants or antidepressants.

[0091] Psychostimulants include, but are not limited to, sympathomimetics —centrally acting (amphetamine, dexamphetamine, methamphetamine, —methylphenidate, —“pemoline, fencamfamine, modafinil, fenozolone, atomoxetine, phenethylline, dexmethylphenidate, lisdexamfetamine), nootropics or other psychostimulants (caffeine, propentofylline, meclofenoxate, pyritinol, piracetam, deanol, fipexide, cytocholine, oxiracetam, pyrisudanol, linopyrdine, nizophenone, aniracetam, acetylcarnitine, idebenone, prolintan, pipradrol, pramiracetam, adrafinil, vinpocetine, tacrine,

34/323 donepezil, rivastigmine, galanthamine, ipidachrine, memantine, mebicar, phenibut).

[0092] Antidepressants include, but are not limited to, non-selective monoamine reuptake inhibitors (desipramine, imipramine, imipramine oxide, clomipramine, opipramol, trimipramine, lofepramine, dibenzepine, amitriptyline, nortriptyline, protriptyline, doxepin, iprindol, melitracene, butriptyline, dosulepin, amoxapine, dimethacrine, aminaptine, maprotiline, quinupramine), serotonin modulator and stimulants (vilazodone, vortioxetiae), selective serotonin reuptake inhibitors (zimeldine, fluoxetine, paroxetine, sertraline, alaproclate, fluvoxamine, etoperidone, citalopram, escitalopram ), non-selective hydrazide-derived monoamine oxidase inhibitors (isocarboxazid, nialamide, phenelzine, tranylcypromine, iproniazid, iprocloside), non-hydrazide monoamine oxidase inhibitors (moclobemide, toloxatone) or other agents (oxitriptan, tryptophan, mianserin, nomifensin, trazodone, nefazodone, minaprine, bifemelane, viloxazine, oxaflozane, mirtazapine, medifoxa mina, tianeptine, pivagabine, venlafaxine, milnacipran, reboxetine, pyrazidol, duloxetine, agomelatine, desvenlafaxine, bupropion, gepirone, Hiperici herbal extract).

[0093] Antihypertensives include, but are not limited to, BB receptor blockers, thiazide diuretics, angiotensin converting enzyme inhibitors, calcium antagonists, angiotensin receptor antagonists (losartan), Rauwolfia alkaloids (rescinnamine, reserpine, deserpidine , metoserpidine, bietaserpine), methyldopa, imidazoline receptor agonists (clonidine, guanfacine, tolonidine, moxonidine, rilmenidine), ganglion anti-adrenergic agents (trimetaphane sulfonium derivative, secondary and tertiary amine mecamylamine), peripherally acting anti-adrenergic agents, alpha-adrenoreceptor (prazosin, indoramine, trimazosine, doxazosin, urapidil), guanidine derivatives (bethanidine, guanethidine, guanoxane, debrisoquine, guanochlor, guanazodine,

guanoxabenz), agents acting on arteriolar smooth muscle, thiazide diazoxide derivative, hydrazinophthalazine derivatives (dihydralazine, hydralazine, endralazine, cadralazine), minoxidil pyrimidine derivative, nitroprusside nitroferricyanide derivative, pinacidyl guanidine derivative, non-Rauwolfia alkaloid veratrum , the tyrosine hydroxylase inhibitor metyrosine, the MAO inhibitor parigiline, the serotonin antagonist ketanserin or other antihypertensives (bosentan, ampbrisentan, sitaxentan, macitentan, riociguat) and a combination of these substances with a diuretic.

[0094] Spasmolytics or antispasmodics include, but are not limited to, peripheral muscle relaxants, curare alkaloids, choline derivatives, other quaternary ammonium muscle relaxants (pancuronium, galamine, vecuronium, atracurium, hexafluronium, pipecuronium bromide, doxacurium chloride , fazadinium bromide, rocuronium bromide, mivacurium bromide, cisatracurium, botulinum toxin), central nervous system muscle relaxants, carbamic acid esters (phenprobamate, carisoprodol, methocarbamol, styramate, febarbamate), oxazole-, thiazine and triazine derivatives — (chlormezanone, — chlorzoxazone), ethers related to antihistamines (orphenadrine, guaifenesin) and other histaminergic agents (such as histamine H receptor antagonists; / inverse agonists, e.g. ciproxifan, thioperamide, pitolisant, clobenpropit, ABT-239, conessin , A-349,821, betahistine), other centrally acting agents (baclofen, arbaclofen, tizanidine, pridinol, tolpe risona, thiocolchicoside, mephenesin, tertazepam, cyclobenzaprine, phenyramidol), the directly acting muscle relaxant dantrolene and six derivatives, compounds acting by increasing GABA-mediated inhibition or decreasing Na* conduction (phenytoin, carbamazepine, lamotrigine, VPA) , gamma-aminobutyric acid derivatives (vigabatrin, gabapentin), other GABAergic agents (such as GABArz PAMs, e.g. ADX71441), esters with a tertiary amino group (oxyphencyclimine, camilofinay mebeverine, trimebutine,

rociverine, dicycloverine, dihexiverine, diphemerine, piperidolate), quaternary ammonium compounds (benzylone, glycopyrronium, oxyphenonium, penthynate, propantheline, othylnium bromide, methantheline, tridihexethyl, isopropamide, hexocyclium, poldine, mepenzolate, bevonium, pipenzolate, difemanil, emetonium, thiemonium iodide, prifinium bromide, timepidium bromide and fenpiverinium), amides with tertiary amines (astra 1397, nicofetamide, tiropramide), papaverine and its derivatives (drotaverinay, moxaverine, etaverine), agents acting on serotonin receptors (alosetron, tegaserod, cilansteron, prucalopride), other agents of functional gastrointestinal disorders — (fenpiprane, diisopromine, chlorbenzoxamine, pinaverine, phenoverine, idanpramine, proxazole, alverine, trepibutone, isometepten, caroverine, phloroglucinol, silicones, trimethyldiphenylpropylamine), sucinimide derivative ( ethosuximide, fensuximide, mesuximide) or Belladonna alkaloids and their derivatives (atropine, h ioscyamine, butylscopolamine, methylatropine, methylscopolamine, fentonium, cimetropium bromide).

[0095] Antiepileptics include, but are not limited to, barbiturates and their derivatives (methylphenobarbital, phenobarbital, primidone, barbexaclone, metarbital), hydantoin derivatives (ethion, phenytoin, amino(diphenylhydantoin) valeric acid, mephenytoin, fosphenytoin), oxazolidine derivatives (paramethadione, — trimethadione, etadion), succinimide derivatives (ethosuximide, fensuximide, mesuximide), benzodiazepine derivative clonazepam, carboxamide derivatives (carbamazepine, oxcarbazepine, rufinamide), fatty acid derivatives (valproic acid, valpromide, aminobutyric acid, vigabatrin , progabid, tiagabine) and other antiepileptics (sultiama, phenacemide, lamotrigine, felbamate, topiramate, gabapentin, fenturide, levetiracetam, zonisamide, pregabalin, stiripentol, lacosamide, charisbamate, retigabine, brivaracetam, beclamide).

[0096] Other agents include, but are not limited to, medicinal products (probiotics, digestive/digestive aids, herbal extracts),

vitamins (both water-soluble and fat-soluble, such as, but not limited to, vitamin A, D3, A, K, B1, B5, B6, B12, C or their derivatives) and nutritional supplements (coenzymes, e.g. Q10, flavonoids, eg resveratrol, lecithin, unsaturated fatty acids including &-3 and n&-6 fatty acids).

[0097] The compounds of the invention can also be used in combination with phosphodiesterase 5 (PDES5) isoenzyme inhibitors, nitric oxide donors, cyclooxygenase inhibitors, other Vla receptor antagonists (such as balovaptan) or L-arginine to the treatment and/or prophylaxis of a disease or condition associated with Vila receptor function.

[0098] The combination composition may comprise the compound of the invention together with another active substance in a single dosage form or separately. The combination composition can be administered simultaneously, separately or sequentially.

[0099] Suitable dosage forms include oral, rectal, mucosal, transdermal or intestinal administration; parenteral administration including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intraarticular, intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injections and eye drops.

[00100] Alternatively, the compounds may be administered locally rather than systemically, for example, by direct injection of the compound into the kidney or heart, often in a modified release formulation. In addition, the drug can be administered in a target-tagged carrier system, for example in a tissue-specific antibody-encapsulated liposome. Liposomes transfer the active substance selectively to the target organ, which absorbs them.

[00101] The pharmaceutical composition can be administered in various modes and in dosage forms. The compound of the invention can be administered alone or in combination with pharmaceutically acceptable excipients, in single or multiple doses. The dose required to achieve the appropriate therapeutic effect can vary widely and must always be adapted to individual needs with regard to the stage of the disease, the condition and weight of the patient being treated, and sensitivity to the active substance, mode of regimen. dosage and numbers of daily treatments.

[00102] For single administration, it is preferred that the pharmaceutical compositions consist of dosage units that contain the amount of the drug to be administered at one time, or a small number of a multiple thereof, or a half, a third, a quarter. Such dosage units are, for example, tablets which may be provided with a half or quarter groove to facilitate the division into half or quarter of the tablet in order to measure the required amount of drug.

[00103] Pharmaceutical compositions containing the active substance according to the invention generally contain from 0.01 to 500 mg of active substance per unit dosage. It is also possible, of course, that the amount of active substance in each formulation exceeds the above or below limit.

[00104] Other preferred groups of compounds of formula (1) are those wherein each of the A ring, B ring, X, 1, Z, R-R*', Cy!-Cy? and m described below are optionally combined. Any combination of the preferred, most preferred or most preferred embodiments of ring A, ring B, X, 1, Z, RI-R*!, Cy!-Cy? or m, as defined below, are also preferred, more preferred, and most preferred groups of compounds of formula (1).

[00105] In certain embodiments of the invention, ring A in compounds of formula (1) is a 4 to 6 membered saturated carbocycle.

[00106] In certain preferred embodiments of the invention, ring A in compounds of general formula (1) is cyclobutyl or cyclohexyl.

[00107] In certain more preferred embodiments of the invention, ring A in compounds of general formula (I) is cyclohexyl.

[00108] In certain embodiments of the invention, ring A in compounds of formula (1) is a 4- to 7-membered saturated heterocyclyl group containing | or 2 N, in which ring A is fixed via a nitrogen in the ring to Y.

[00109] In certain embodiments of the invention, ring A in compounds of formula (1) is a 4- to 7-membered saturated heterocyclyl group containing 1 or 2 N, in which ring A is attached via a nitrogen in the ring to the triazole ring of the 5,6-dihydro-4H-[1,24]triazolo[4,3-a][1]benzazepine core.

[00110] In certain embodiments of the invention, ring A in compounds of general formula (1) is azetidinyl, 1,3-diazetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, azepanyl, 1,3- or 1,4-diazepanyl , in which ring A is fixed via a nitrogen in the ring to Y.

[00111] In certain embodiments of the invention, ring A in compounds of formula (1) is azetidinyl, 1,3-diazetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, azepanyl, 1,3- or 1,4-diazepanyl , in which ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine nucleus.

[00112] In certain preferred embodiments of the invention, ring A in compounds of general formula (1) is azetidin-1,3-diyl, piperidin-1,4-diyl or piperazine-14-diyl, wherein ring A is attached via a nitrogen in the ring to Y or the triazole ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine nucleus.

[00113] In certain embodiments of the invention, ring B in compounds of general formula (1) is an optionally substituted aryl group.

[00114] In certain preferred embodiments of the invention, ring B in compounds of general formula (1) is optionally substituted phenyl.

[00115] In certain embodiments of the invention, ring B in compounds of general formula (1) is an optionally substituted heterocyclyl group.

40 / 323

[00116] In certain preferred embodiments of the invention, ring B in compounds of general formula (1) is optionally substituted tetrahydrofuranoyl, tetrahydropyranoyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or azabicyclo[2,2,2]octyl.

[00117] In certain more preferred embodiments of the invention, ring B in compounds of general formula (1) is tetrahydrofuran-3-yl, tetrahydropyran-4-yl, pyrrolidin-1-yl, pyrrolidin-1-11-2-one, piperidin-11-yl, 4-methyl-piperazin-1-yl, morpholin-4-yl or 1-azabicyclo[2.2.2]oct-3-yl.

[00118] In certain embodiments of the invention, ring B in compounds of general formula (1) is an optionally substituted heteroaryl group.

[00119] In certain embodiments of the invention, ring B in compounds of general formula (1) is optionally substituted with a single 6- or membered monoheteroaryl group.

[00120] In certain preferred embodiments of the invention, ring B in compounds of general formula (1) is optionally substituted pyridinyl, pyrimidinyl or isoxazolyl.

[00121] In certain more preferred embodiments of the invention, ring B in compounds of general formula (1) is pyridin-2yl, pyridin-3-yl, 3-chloropyridin-2-yl, 3-methyl-pyridin-2-1la, pyrimidin-2-yl or 5-methyl-isoxazol-3-yl.

[00122] In certain most preferred embodiments of the invention, ring B in compounds of general formula (1) is pyridin-2-yl.

[00123] In certain embodiments of the invention, Y in compounds of formula (1) is -O- if ring B is present.

[00124] In certain embodiments of the invention, Y in compounds of formula (1) is -C(O)- if ring B is present.

[00125] In certain embodiments of the invention, Y in compounds of general formula (1) is -CHz-, if ring B is present.

[00126] In certain embodiments of the invention, Y in the compounds of

The general formula (1) is -NH-, if ring B is present.

[00127] In certain embodiments of the invention, Y in compounds of formula (1) is -Cr4alkyl-N(R'*)-, if ring B is present.

[00128] In certain preferred embodiments of the invention, Y in compounds of general formula (I) is a single bond, if ring B is present.

[00129] In certain embodiments of the invention, Y in compounds of general formula (DD is -N(Cyalkyl, C(O)JOC ,alkyllay, Crayalkyl optionally substituted with halogen, C1,4alkoxy group or halogen, if ring B is not gift.

[00130] In certain embodiments of the invention, Y in compounds of general formula (1) is C1,alkyl optionally substituted with halogen or C,alkoxy group, if ring B is not present.

[00131] In certain preferred embodiments of the invention, Y in compounds of general formula (1) is C1-3 alkyl group, if ring B is not present.

[00132] In certain more preferred embodiments of the invention, Y in the compounds of general formula (1) is methyl, ethyl, or propyl group, if ring B is not present.

[00133] In certain preferred embodiments of the invention, Y in the compounds of general formula (1) is C1-3alkoxy group, if ring B is not present.

[00134] In certain more preferred embodiments of the invention, Y in the compounds of general formula (1) is methoxy or ethoxy group, if ring B is not present.

[00135] In certain preferred embodiments of the invention, Y in compounds of general formula (1) is CF3 group, if ring B is not present.

[00136] In certain embodiments of the invention, Y in compounds of general formula (DI), if ring B is not present, refers to a group selected from the group consisting of -N(C,4alkyl)o, C(O0 )C14 alkyl, C14 alkyl optionally substituted with halogen, C11 alkoxy group and halogen.

[00137] In certain preferred embodiments of the invention, Y in the compounds of general formula (1), if ring B is not present, refers to a group selected from the group consisting of dimethylamine, group C(O)OC, ., alkyl and CF; group.

[00138] In certain embodiments of the invention, Y in the compounds of general formula (1), if ring B is not present, refers to two groups selected from the group consisting of C1-alkyl optionally substituted with halogen, Cr,4alkoxy group and halogen.

[00139] In certain preferred embodiments of the invention, Y in the compounds of general formula (1), if ring B is not present, refers to two groups selected from the group consisting of C 1 3 alkyl, C 1 3 alkoxy, CF group; and fluorine.

[00140] In certain more preferred embodiments of the invention, Y in the compounds of general formula (1), if ring B is not present, refers to two groups selected from the group consisting of methyl, ethyl, propyl, methoxy, ethoxy group , CF; and fluorine.

[00141] In certain even more preferred embodiments of the invention, Y in the compounds of general formula (1), if ring B is not present, refers to two groups selected from the group consisting of methyl, ethyl, propyl, methoxy and ethoxy.

[00142] In certain preferred embodiments of the invention, in compounds of general formula (ID), ring A is cyclobutyl or cyclohexyl, Y refers to a group selected from the group consisting of -N(C 4 alkyl) 2 , -C(0)OC. alkyl, CF; and halogen and B ring is not present.

[00143] In certain preferred embodiments of the invention, in the compounds of general formula (1), ring A is cyclobutyl or cyclohexyl, Y refers to two groups selected from the group consisting of Cr., alkyl optionally substituted with halogen, Ci group, alkoxy and halogen and ring B is not

43 /323 present.

[00144] In certain preferred embodiments of the invention, in the compounds of general formula (1), ring A is cyclobutyl or cyclohexyl, Y is -O- or bond, and ring B is optionally substituted phenyl, piperidin-1-yl, morpholin -4-yl, 1-azabicyclo[2,2,2]oct-3-yl, pyridin-2-yl, pyridin-3-yl, 3-chloro-pyridin-2-yl, 3-methylpyridin-2-yl , pyrimidin-2-yl or 5-methylisoxazol-3-yl.

[00145] In certain more preferred embodiments of the invention, in the compounds of general formula (1), ring A is cyclohexyl, Y is -O- and ring B is pyridin-2-yl, — pyridin-3-yl, — 3-chloro-pyridin-2-yl, — 3-methylpyridin-2-yl, pyrimidin-2-11 or 5-methylisoxazol-3-yl.

[00146] In certain most preferred embodiments of the invention, in the compounds of general formula (1), ring A is cyclohexyl, Y is -O- and ring B is pyridin-2-yl.

[00147] In certain preferred embodiments of the invention, in compounds of formula (D), ring A is azetidin-1,3-diyl, piperidin-1,4-diyl or piperazine-14-diyl, wherein ring A is fixed via a ring nitrogen to Y or the triazole ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine nucleus, Y is -O- or bond and ring B is optionally substituted phenyl, —piperidin-1-yl, morpholin-4-yl, 1-azabicyclo[2,2,2]oct-3-yl, pyridin-2-yl, pyridin-3-yl, 3-chloro-pyridin-2-yl, 3-methylpyridin-2-yl, pyrimidin-2-11 or 5-methylisoxazol-3-yl.

[00148] In certain more preferred embodiments of the invention, in the compounds of formula (1), ring A is piperidin-1,4-diyl or piperazine-1,4-diyl, wherein ring A is fixed via a nitrogen on the ring to Y or the triazole ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine nucleus, Y is -O- or bond and ring B is pyridin -2-yl or pyridin-3-yl.

[00149] In certain embodiments of the invention, in compounds of general formula (1), ring A is cyclobutyl, cyclohexyl or pyrrolidinyl, Y is -C(O)- and ring B is pyrrolidin-1-yl, piperidin-1 -yl, morpholin-4-yl, 4-methyl-piperazinyl

44 / 323 or pyridine-3-yl.

[00150] In certain embodiments of the invention, BYA- in the compounds of general formula (1) together represents 3H-spiro[2-benzofuran-1,4'-piperidin-1*-11], 1-Oxa-3-azaspiro[ 4,5 ]decan-2-on-8-yl substituted at position 3 by C14 alkyl or 2-azaspiro[4,5]decan-1-on-8-yl substituted at position 2 at C, ,alkyl, aryl or heteroaryl .

[00151] In certain preferred embodiments of the invention, BYA- in the compounds of general formula (1) together represents 3H-spiro[2-benzofuran-1 4'-piperidin-1"-yl], (5S8,8S)-3- methyl-1-oxa-3-azaspiro[4.5]decan-2-on-8-yl, (5R,8R)-3-methyl-1-oxa-3-azaspiro[4.5 decan-2-on -8-yl, (5R,8R)--2-(propan-2-11)-2-azaspiro[4.5]decan-1-one or (55.85)-2-(propan-2-11 )-2-azaspiro[4,5]decan-1-one.

[00152] In certain embodiments of the invention, R' in compounds of general formula (1) is hydrogen.

[00153] In certain embodiments of the invention, R' in compounds of general formula (1) is halogen.

[00154] In certain preferred embodiments of the invention, R' in compounds of general formula (1) is chlorine, bromine or fluorine.

[00155] In certain more preferred embodiments of the invention, R' in the compounds of general formula (I) is chloro.

[00156] In certain embodiments of the invention, R' in the compounds of formula (1) is C1,alkyl.

[00157] In certain preferred embodiments of the invention, R' in compounds of formula (1) is methyl.

[00158] In certain embodiments of the invention, R' in compounds of formula (1) is Cr,alkoxy

[00159] In certain preferred embodiments of the invention, R' in compounds of formula (1) is methoxy.

[00160] In certain embodiments of the invention, R' in the compounds of

45 /323 general formula (1) is CF3.

[00161] In certain embodiments of the invention, R' in compounds of formula (1) is CN.

[00162] In certain embodiments of the invention, in compounds of general formula (D), R? is hydrogen or C1,alkyl, R? is NRR5, OR group” or halogen.

[00163] In certain embodiments of the invention, in compounds of general formula (1), Rº is Cr,4alkyl, Rº is NRÍRS, OR" group or halogen.

[00164] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is NRR;, OR” or halogen group.

[00165] In certain preferred embodiments of the invention, in the compounds of general formula (1), R? is hydrogen, R? is NRºR or &rº OR and the absolute configuration of the carbon at position 5 on the 5,6-dihydro-4H-[1,2A]triazolo[4,3-a][1|benzazepine nucleus is (R).

[00166] In certain embodiments of the invention, in compounds of general formula (1), Rº is hydrogen, R? is NRR or OR group" and the absolute configuration of the carbon at position 5 on the 5,6-dihydro-4H-[1,24]triazolo[4,3-a][1]benzazepine nucleus is (S).

[00167] In certain embodiments of the invention, in compounds of general formula (D, R' is hydrogen, R' is NR'R' or group OR".

[00168] In certain embodiments of the invention, in compounds of general formula (D), Rº is hydrogen, R? is NRÍRS group.

[00169] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen or C1,4alkyl group, Rº is NRR5 group, where Rº and Rº are hydrogen.

[00170] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is NRRº group, where Rº is hydrogen, R is Ci,alkyl group.

[00171] In certain preferred embodiments of the invention, in the compounds

46 / 323 of general formula (1), Rº is hydrogen, R? is NRRS group, where Rº is hydrogen R* is isopropyl group.

[00172] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is NRró group, where Rº and R$ are C ,4alkyl groups.

[00173] In certain preferred embodiments of the invention, in compounds of general formula (), R? is hydrogen, R? is group NR(RS, where R° and RÉ are independently a methyl, ethyl or isopropyl group.

[00174] In certain more preferred embodiments of the invention, in the compounds of general formula (1), R? is hydrogen, Rº is NRÍR5 group, where Rº and R6 are methyl groups.

[00175] In certain embodiments of the invention, in compounds of general formula (1), Rº is hydrogen, R? is NRR' group, where Rº is hydrogen, Rº is Cr group, OH-substituted alkyl.

[00176] In certain preferred embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is NRÍRS group, where Rº is hydrogen, Rº is hydroxymethyl or hydroxyethyl group.

[00177] In certain embodiments of the invention, in compounds of general formula (D), Rº is hydrogen, R? is group NRR$, where R° is hydrogen, Ri is group Cr, halo-substituted alkyl.

[00178] In certain preferred embodiments of the invention, in compounds of formula (D), R? is hydrogen, R? is NRÍR group, where Rº is hydrogen, R* is trifluoro-substituted C,2alkyl group.

[00179] In certain preferred embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is NRÍRS group, where Rº is hydrogen, R* is methyl-cyclopropyl group.

[00180] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is NRRI group, where R is hydrogen, Rº is 4-fluorophenyl-substituted methyl or ethyl group.

47 /323

[00181] In certain embodiments of the invention, in compounds of general formula (D), Rº is hydrogen, R? is group NRR;, where Rº is hydrogen, Ró is Cialkyl substituted with group NRºRº, where Rº and Rº are independently hydrogen, group C, ..alkyl or group C(0)JOR”!.

[00182] In certain preferred embodiments of the invention, in compounds of formula (D), R? is hydrogen, R? is group NRÍR, where Rº is hydrogen, Rº is Ciaalkyl substituted with group NRºRº, where Rº is hydrogen, Rº is group C(O0)OR?'.

[00183] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is NRRº group, where Rº is hydrogen, Ró is Cialkyl substituted with NRºRº group, where Rº and Rº are independently hydrogen or C, ,alkyl group.

[00184] In certain preferred embodiments of the invention, in compounds of general formula (1), R° is hydrogen, R? is NRÍRS group, where Rº is hydrogen, R” is aminomethyl or ethyl group.

[00185] In certain preferred embodiments of the invention, in compounds of general formula (1), R° is hydrogen, R? is NRRS group, where Rº is hydrogen, Rº is dimethylamino-methyl or ethyl group.

[00186] In certain embodiments of the invention, in compounds of general formula (D), R? is hydrogen, R? is group NRR;, where Rº is hydrogen, RéCy.

[00187] In certain preferred embodiments of the invention, in compounds of general formula (D), R? is hydrogen, R? is NRRIRI group, where Rº is hydrogen, Rº is cyclobutyl, cyclopentyl, cyclohexyl, 4,4-difluoro-cyclohexyl, oxetan-2-yl or tetrahydropyranoyl.

[00188] In certain preferred embodiments of the invention, in compounds of general formula (1), R° is hydrogen, R? is group NRÍRS, where Rº is hydrogen, R is pyridin-2-yl, pyrimidin-2-yl or pyrazin-2-yl.

[00189] In certain embodiments of the invention, in the compounds of

48 /323 general formula (D), R? is hydrogen, R? is group NRR$, where Rº is hydrogen, R is group C(O)R?, where R? is methyl, ethyl or isopropyl group.

[00190] In certain embodiments of the invention, in compounds of general formula (D), Rº is hydrogen, R? is group NRR$, where Rº is hydrogen, Rº is group C(O)R, where Rº is Ci,alkyl substituted with group OH, CN, halogen, Cy? or NRUR”?.

[00191] In certain preferred embodiments of the invention, in compounds of general formula (1), R° is hydrogen, R? is group NRÍRS, where Rº is hydrogen, R is group C(O)R, where R? is methyl, ethyl or isopropyl group substituted with OH, CN or trifluoro.

[00192] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is NRri group, where R is hydrogen, R is C(O)R group, where R? is methyl or ethyl substituted with NRUR group”, where R!' and R!? are independently hydrogen or methyl or R'' and R'' taken together with the N to which they are attached form morpholin-4-yl or 4-methyl-piperazin-1-yl.

[00193] In certain preferred embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is NRRS group, where Rº is hydrogen, Rº is C(O)R7 group, where R' is amino methyl group.

[00194] In certain preferred embodiments of the invention, in compounds of formula (D), R? is hydrogen, R? is NRRIRI group, where Rº is hydrogen, R* is C(O)R7 group, where R7 is dimethylaminomethyl group.

[00195] In certain preferred embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is group NRÍRS, where Rº is hydrogen, Rº is group C(O)R', where Rº is phenyl and/or NH 2 -substituted methyl.

[00196] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is NRRi group, where R is hydrogen, Ri is C(O)R' group, where R' is t-butoxy group.

49 / 323

[00197] In certain embodiments of the invention, in compounds of general formula (D), Rº is hydrogen, R? is group NRR$, where Rº is hydrogen, Ró is group C(O)R?, where R? It's a vinyl group.

[00198] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is NR6 group, where Rº is hydrogen, R is C(O)RI group, where R' is Cy*? group.

[00199] In certain preferred embodiments of the invention, in compounds of general formula (1), R° is hydrogen, R? is group NRÍRS, where Rº is hydrogen, Rº is group C(O)R7, where R? is 4-fluorophenyl, cyclopropyl, cyclobutyl, dihalo-cyclobutyl or cyclohexyl, oxetanyl, tetrahydropyran-4yl, 4-methyl-piperidinyl, or 5-methyl-1,3,4-oxadiazol-2-yl.

[00200] In certain preferred embodiments of the invention, in compounds of formula (1), R? is hydrogen, R?º is group NRR5, where Rº is hydrogen, R* is group C(O)R7, where R? is dimethylamino group.

[00201] In certain preferred embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is NRRS group, where Rº is hydrogen or methyl, Rº is -S(O3)R"!º, where R"º is methyl, OH, NH, NH-r-butyl group, or dimethylamino.

[00202] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is NRR5 group, where Rº is hydrogen or C1,alkyl group, R* is Cz.1alkynyl group.

[00203] In certain preferred embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is NRÍRS group, where Rº is methyl group, R6 is propargyl group.

[00204] In certain embodiments of the invention, in compounds of general formula (1), Rº is hydrogen, R? is group NRR$, where Rº and R* taken together with the N to which they are attached form a 4- to 7-membered heterocycle optionally containing one or more heteroatoms selected from O, S or N.

[00205] In certain preferred embodiments of the invention, in the compounds of general formula (D, R? is hydrogen, Rº is NRR5, where Rº and Ró taken together with the N to which they are attached form pyrrolidine, piperidine, piperazine, morpholine , 1,3-oxazolidine, 1,3-thiazolidine or thiomorpholine-1,1-oxide.

[00206] In certain preferred embodiments of the invention, in compounds of general formula (D), Rº is hydrogen, R?º is group ORS$, where R$ is hydrogen.

[00207] In certain preferred embodiments of the invention, in compounds of general formula (1), Rº is hydrogen, R? is OR group”, where R$ is a methyl, ethyl or isopropyl group.

[00208] In certain more preferred embodiments of the invention, in the compounds of formula (1), R? is hydrogen, R? is ORS group, where Rº is methyl group.

[00209] In certain embodiments of the invention, in compounds of general formula (D), R? is hydrogen, R? is OR group”, where R$ is OH- or C1,alkyl group substituted by halogen.

[00210] In certain preferred embodiments of the invention, in compounds of formula (D), R? is hydrogen, R? is ORS group, wherein R6 is chloro- or fluoro-substituted methyl or ethyl group.

[00211] In certain embodiments of the invention, in compounds of general formula (D), R? is hydrogen, Rº is ORS group, where R$ is cyclopropyl-methyl group.

[00212] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R?º is an OR group, where R$ is C1, alkyl substituted with Cr, alkoxy group.

[00213] In certain preferred embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is an OR group”, where Rº is a methoxy-ethyl group.

[00214] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is ORS group, wherein R° is C1,4 alkyl substituted with Cr.,alkyl-S(O), group.

[00215] In certain preferred embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is OR group”, where R$ is methylsulfonyl-ethyl group.

[00216] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is group OR, where Rº is methyl or ethyl substituted with group NRUR"”?, where R!' and R1? are independently hydrogen or methyl.

[00217] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R?º is an OR group, where Rº is methyl or ethyl substituted with NRUR"?, where R"' is R!? taken together with the N to which they are attached form a morpholin-4-yl.

[00218] In certain preferred embodiments of the invention, in compounds of general formula (D), R? is hydrogen, R? is OR group", where R6 is dimethylamino-ethyl group.

[00219] In certain embodiments of the invention, in compounds of general formula (1), Rº is hydrogen, R? is group ORS, where Rº IS C(O)R"?, where R'"? is Cr.,alkyl group.

[00220] In certain preferred embodiments of the invention, in compounds of general formula (D), R? is hydrogen, R? is group OR”, where R° is C(O)R"?, where R'" is methyl, ethyl or r-butyl.

[00221] In certain embodiments of the invention, in compounds of general formula (DI), R? is hydrogen, R? is group ORS, where R° is C(O)R", where R"? is group C, alkyl substituted with CN.

[00222] In certain preferred embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is OR" group, where R$ is C(O)R"?, where R" is cyanomethyl group.

[00223] In certain embodiments of the invention, in compounds of general formula (1), Rº is hydrogen, R? is group ORS, where Rº IS C(O)R"?, where R'"? is C1 group, alkyl substituted with NR/ºR group”.

[00224] In certain preferred embodiments of the invention, in compounds of formula (D), R? is hydrogen, R? is group OR”, where Rº is C(O)R"?, where R"? is dimethylamino-methyl group.

[00225] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is group ORS, where Rº IS C(O)R"?, where R" is group Cy*?.

[00226] In certain preferred embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is OR" group, wherein R° is C(O)R"?, wherein R'? is dihalo-substituted cycloalkyl group.

[00227] In certain embodiments of the invention, in compounds of general formula (1), Rº is hydrogen, R? is ORS group, where R° is C(O)R"?, where R'? is NR'R", where R'° R" is independently hydrogen, Cr.1alkyl, or optionally substituted aryl.

[00228] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is group OR, where Rº is C(O)R"?, where R"? is NR'ºR"!, where R'* and R" taken together with the N to which they are attached form a piperidine or pyrrolidine.

[00229] In certain embodiments of the invention, in compounds of general formula (1), Rº is hydrogen, Rº is OR group, where Rº is Si(CH;3)2-1-butyl.

[00230] In certain embodiments of the invention, in compounds of general formula (1), R? is hydrogen, R? is ORS group, where R$ is Cx. 1alkynyl group.

[00231] In certain preferred embodiments of the invention, in compounds of general formula (1), R° is hydrogen, R? is an OR group”, where R$ is a propargyl group.

[00232] In certain embodiments of the invention, in compounds of general formula (D, R₂ is C1,alkyl, R₂ is NR₁₂ or OR group.

[00233] In certain embodiments of the invention, in the compounds of general formula (D, R° is C1,1 alkyl, R' is OR group.

[00234] In certain embodiments of the invention, in compounds of general formula (1), one of R? and Ro? is methyl or isopropyl, the other is ORO, where Rº is hydrogen.

[00235] In certain embodiments of the invention, in compounds of general formula (1), Rº is hydrogen and R? it's halogen.

[00236] In certain preferred embodiments of the invention, in compounds of formula (1), R? is hydrogen and R? it's fluorine.

[00237] In certain embodiments of the invention, in the compounds of general formula (1), R6 is Cr ,4alkyl and R? it's halogen.

[00238] In certain preferred embodiments of the invention, in the compounds of general formula (1), R? and R6 together represent -O-(CH>).n-O- and m = 2,3 or 4.

[00239] In certain more preferred embodiments of the invention, in the compounds of general formula (D), R° and R? together they represent -O-(CHo)1-O- at =2.

[00240] In certain preferred embodiments of the invention, in compounds of general formula (1), R? and R?º together represent a 0x0 group.

[00241] In certain embodiments of the invention, in compounds of general formula (D), R? and R? together they represent a =N-OH group.

[00242] While the invention has been described in connection with some embodiments, some preferred, most preferred or most preferred embodiments, it is not intended to limit the scope of the invention to the particular form specified, but rather, it is intended to cover all of such alternatives, modifications, and equivalents as may be included within the scope and spirit of the invention, as defined by the statements of the

54 /323 invention. Examples of alternative claims directed to the compounds of the present invention may include:

[00243] (1) The compounds of general formula (1) as described above, or in any other embodiment.

[00244] (2) The compound as described in (1), or in any other embodiment, wherein R' is a hydrogen, fluorine, chlorine, bromine, methyl, methoxy, CF group; or CN.

[00245] The compound as described in any one of (1) to (2), or in any other embodiment, wherein ring A is a 3 to 6 membered saturated carbocyclic or a 4 to 7 membered saturated heterocycle containing | or 2N; ring B is an optionally substituted 5 or 6 membered monoheteroaryl, 6 to 10 membered aromatic carbocycle, or saturated, monocyclic, bicyclic, condensed and/or bridged 4 to 7 membered heterocycle containing 1, 2 or 3 heteroatoms selected from O, S or N; or B-Y-A- together represent a zN Na 3/H-spiro[2-dr benzofuran-1 4"-piperidin-1"-yl]; or YO group, or “O.

DN or DO group.

X is isopropyl group; Z is methyl group.

[00246] (4) The compound as described in any one of (1) to (3), or in any other embodiment, wherein ring B is an optionally substituted 6-membered monoheteroaryl, phenyl, or saturated monocyclic heterocycle group of 5 to 6 members containing 1 or 2 heteroatoms selected from O, Sou N.

[00247] (5) The compound as described in any one of (1) to (4), or in any other embodiment, wherein Y is -O-, -C(OO)-, -CH7 >-, -NH -, -C1.

alkyl-N(R'*)- or a single bond if ring B is present and R!? is a hydrogen or methyl group.

[00248] (6) The compound as described in any one of (1) to (5), or in any other embodiment, wherein ring A is a 4 to 6 membered saturated carbocyclic group or a 4 to 7 membered saturated heterocycle 1 or 2 N-containing members fixed via a nitrogen ring to the Y or the triazole ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine nucleus.

[00249] (7) The compound as described in any one of (1) to (6), or in any other embodiment, wherein ring A is a cyclohexyl group, Y is -O-, ring B is a pyridin -2-yl and R' is chloro.

[00250] (8) The compound as described in any one of (1) to (6), or in any other embodiment, wherein ring A is a piperidine, piperazine, or pyrrolidine, Y is -O-, -C( OO)-, -CH2-, or a single bond, ring B is a pyridine, piperidine, tetrahydrofuran, or tetrahydropyran and R' is chloro.

[00251] (9) The compound as described in any one of (1) to (3), or in any other embodiment, wherein Y is -N(Ci,4alkyl)o, C(O)OC 4alkyl, Ci, alkyl optionally substituted with halogen, C1, alkoxy or halogen group and ring B is not present.

[00252] (10) The compound as described in (9), or in any other embodiment, wherein ring A is a 4- to 6-membered saturated carbocyclic group.

[00253] (11) The compound as described in (10), or in any other embodiment, wherein Y is a group selected from the group consisting of -N(C 4 alkyl), C(O)OC ,alkyl, Ci, 4alkyl optionally substituted with halogen, C₂ group, alkoxy and halogen.

[00254] (12) The compound as described in (10), or in any other embodiment, wherein Y is two groups selected from the group consisting of C1,alkyl optionally substituted with halogen, C14alkoxy group, and halogen.

[00255] (13) The compound as described in any one of (1) to (12), or in any other embodiment, wherein R? is a hydrogen or C1 group. aalkyl and Rô is an NRR$ group.

[00256] (14) The compound as described in (13), or in any other embodiment, wherein R? it's a hydrogen.

[00257] (15) The compound as described in (14), or in any other embodiment, wherein Rº and Ró is independently a hydrogen; COLOR; C. 1alkyl optionally substituted with OH group, halogen, cycloalkyl, optionally substituted aryl or NRºRº.

[00258] (16) The compound as described in (15), or in any other embodiment, wherein Rº and R* are hydrogens.

[00259] (17) The compound as described in (15), or in any other embodiment, wherein R* is a hydrogen, R6 is a C, ,alkyl group.

[00260] (18) The compound as described in (15), or in any other embodiment, wherein R6 and R6 are C1,alkyl groups.

[00261] (19) The compound as described in (15), or in any other embodiment, wherein Rº is a hydrogen, R* is a C(O)R7 group.

[00262] (20) The compound as described in (14), or in any other embodiment, wherein Rº is a hydrogen, Rº is Cy.

[00263] (21) The compound as described in (14), or in any other embodiment, wherein Rº is a hydrogen or C1,alkyl, Rº is an S(O02)R"º group.

[00264] (22) The compound as described in (14), or in any other embodiment, wherein R* and Rº taken together with the N to which they are attached form a 4- to 7-membered heterocycle optionally containing 1, 2 or 3 heteroatoms selected from O, S or N.

[00265] (23) The compound as described in any one of (1) to (12), or in any other embodiment, wherein R? is a hydrogen or C1 group. alkyl; R? is an OR group.

[00266] (24) The compound as described in (23), or in any other embodiment, wherein R? it's a hydrogen.

[00267] (25) The compound as described in (24), or in any other embodiment, wherein Rº is a hydrogen.

[00268] (26) The compound as described in (24), or in any other embodiment, wherein R6 is a C1,4 alkyl group.

[00269] (27) The compound as described in (24), or in any other embodiment, wherein R° is a C(O)R"? group.

[00270] (28) The compound as described in any one of (13) to (27), or in any other embodiment, wherein the absolute configuration of the carbon at position 5 in the nucleus is 5,6-dihydro-4H- [1,2,4]triazolo[4,3-a][1]benzazepine is (R).

[00271] (29) The compound as described in any one of (13) to (27), or in any other embodiment, wherein the absolute configuration of the carbon at position 5 in the nucleus is 5,6-dihydro-4H- [1,2,4]triazolo[4,3-a][1]benzazepine is (S).

[00272] (30) The compound as described in any one of (1) to (12), or in any other embodiment, wherein R? and R? together represent -O-(CH2)m-O-, oxo group or =N-OH, m is 2, 3,4 or 5.

[00273] (31) The compound as described in (30), or in any other embodiment, wherein R? and R? together represent -O-(CH> 2 )n-O- and m? group.

[00274] A preferred group of compounds of general formula (1) of the present invention are, for example, the following compounds and/or salts and/or solvates and/or hydrates and/or polymorphs and/or biologically active metabolites and/or prodrugs thereof:

1. [8-Chloro-1-[1-(pyridin-2-yl)piperidin-4-11]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a] [1]benzazepin-5-yl] tert-butyl carbamate,

2. —B8-Chloro-1-[1-(pyridin-2-yl)piperidin-4-11]-5,6-dihydro-4H-

[1,2 4]triazolo[4,3-a][1 Ibenzazepine-5-amine,

3. N-[8-Chloro-[1-(pyridin-2-yl)piperidin-4-11]-5,6-dihydro-4H-[1,24]triazolo[4,3-a] [1]Benzazepin-5-yl Jacetamide,

4. N-(8-Chloro-[1-(pyridin-2-yl)piperidin-4-11]-5,6-dihydro-4H-[1,24]triazolo[4,3-a] [1 Ibenzazepin-5-11)-2-methylpropanamide,

5. (8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a ][1 Ibenzazepine-5-yl | tert-butyl carbamate,

6. 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a] [1]|benzazepine-5-amine,

7. (5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1 Ibenzazepine-5-amine,

8. (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3 -a][1 |benzazepine-5-amine,

9. —“N-(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4] ,3-a][1]benzazepin-5-yl)Jacetamide,

10. N-(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3 -a][1]benzazepin-5-yl)|glycinamide,

11. N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepin-5-yl)glycinamide,

12. N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazole [4,3-a][1]benzazepin-5-yl)glycinamide,

13. (25)-2-amino-N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- [1,2 A4]triazolo[4,3-a][1]benzazepin-5-11)-2-phenylacetamide,

14. (2R)-2-amino-N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- [1,2 A]triazolo[4,3-a][1]benzazepin-5-11)-2-phenylacetamide,

15. N-(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3- a][1]benzazepin-5-yl)-2-hydroxyacetamide,

59 /323

16. 3-(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3 -a][1]benzazepin-5-11)-1,1-dimethylurea,

17. N-(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3 -a][1]benzazepin-5-yl)-No.N-dimethylglycinamide,

18. N-(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3] -a][1]|benzazepin-5-yl)methanesulfonamide,

19. N-(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3 -a][1]benzazepin-5-11)-N-methylmethansulfonamide,

20. N-(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3 -a][1 Ibenzazepin-5-yl)-N,N-dimethylsulfamide,

21. 8-Chloro-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4, 3-a][1]benzazepine-5-amine,

22. 8-Chloro-N,N-dimethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[ 4,3-a][1]benzazepine-5-amine,

23. 8-Chloro-N-ethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4, 3-a][1]benzazepine-5S-amine,

24. —8-Chloro-N-(propan-2-11)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 ,A4]triazolo[4,3-a][1]benzazepine-5-amine,

25. (5S)-8-chloro-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 4] triazolo[4,3-a][1 |benzazepine-5-amine,

26. (5R)-8-chloro-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 4]triazolo[4,3-a][1 Ibenzazepine-5-amine,

27. 8-Chloro-N-cyclobutyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4, 3-a][1 |benzazepine-5-amine,

28. —8-Chloro-N-(oxetan-3-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 ,A]triazolo[4,3-a][1]benzazepine-5-amine,

60 /323

29. 8-Chloro-1-[trans-4-(pyridin-2-1loxy)cyclohexyl]-N-(tetrahydro-2H-pyran-4-11)-5,6-dihydro-4H -[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine,

30. 8-Chloro-N-(4,4-difluorocyclohexyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1, 24]triazolo[4,3-a][1|benzazepine-5-amine,

31. 8-Methoxy-11-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3- hydrochloride a][1 |benzazepine-5-amine,

32. 8-Methoxy-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2, A4]triazolo[4,3-a][1 |benzazepine-5-amine,

33. tert-butyl (11-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,A4]triazolo[ 4,3-a][1 Ibenzazepin-5-yl J|carbamate of,

34. 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,A4]triazolo[4, 3-a][1]|benzazepine-5-amine,

35. N,N-dimethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,A4] triazolo[4,3-a][1]benzazepine-5-amine,

36. N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1, 2,4]triazolo[4,3-a][1]benzazepine-5-amine,

37. 8-Methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a] [1 |benzazepine-5-amine,

38. —Δ8-Methyl-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 ,A4]triazolo[4,3-a][1]benzazepine-5-amine,

39. 8-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a] [1 |benzazepine-5-amine,

40. 8-bromo-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclo-

hexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1]benzazepine-5-amine,

41. 8-Chloro-1-(3,3-difluorocyclobutyl)-N-(propan-2-yl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a ][1]benzazepine-5-amine,

42. 8-Chloro-1-(4,4-difluorocyclohexyl)-N-(propan-2-yl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3 -a][1 |benzazepine-5-amine,

43. 8-Chloro-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepine -5-amine,

44. 8-Chloro-N-(propan-2-yl)-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[ 4,3-a][1|benzazepine-5-amine,

45. 8-bromo-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1|benzazepine- 5-amine,

46. —8-bromo-N-(propan-2-yl)-1-[trans-4-(trifuoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazole [4,3-a][1]benzazepine-5-amine,

47. 1'-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8'-(trifluoromethyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'- [1,2,4]triazolo[4,3-a][1]benzazepine],

48. 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-4H-[1,2,A]triazolo[4,3-a][1]benzazepin-S (6H)-one,

49. 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,A]triazolo[4,3- a][1]benzazepin-5-ol,

50. S-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1]benzazepine,

51. 5-(cyclopropylmethoxy)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,4] triazolo[4,3-a][1]benzazepine,

52. 5-([tert-butyl(dimethyl)silylJoxy)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2,A4]triazolo[4,3-a][1]benzazepine,

53. —8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl |-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1, 2,4]triazolo[4,3-a][1]benzazepine],

54. 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]--4H-

[1,2 4]triazolo[4,3-a][1 Ibenzazepin-S(6H)-one,

55. 8-Chloro-1-[trans-4-(pyridin-2-1loxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a] [1]benzazepin-5-ol,

56. (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1 ]|benzazepin-5-ol,

57. (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1]benzazepin-5-ol,

58. 8-Chloro-S-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4]triazolo[4,3 -a][1 Ibenzazepine,

59. 5-(cyclopropylmethoxy)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4 ,3-a][1 Ibenzazepine,

60. 2-((8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3 -a][1]benzazepin-5-ylJoxy)-N,N-dimethylethanamine,

61. 8'-Chloro-1"-[trans-4-(trifluoromethyl)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4 ]triazolo[4,3-a][1]benzazepine],

62. 8-bromo-1"-[trans-4-(pyridin-2-yloxy)cyclohexyl]|-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1 ,2,4]triazolo[4,3-a][1]benzazepine],

63. 1'-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4] triazolo[4,3-a][1]benzazepine],

64. 8-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]|-4H-[1,24]triazolo[4,3-a][1Ibenzazepin-5(6H) -one,

65. 8-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a] [1 Ibenzazepin-5-ol,

66. 1'-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,24]triazole [4,3-a][1]benzazepin]-8'-carbonitrile,

67. (55)-8-chloro-N,N-dimethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2, A]triazolo[4,3-a][1]benzazepine-5-amine,

68. (5S)-N-(8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-

5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-11)acetamide,

69. 8'-Chloro-1'-[trans-4-(pyridin-2-ylmethyl)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1 ,2,4]triazolo[4,3-a][1]benzazepine],

70. [trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,24]triazolo[4,3-a][1] Ibenzazepine]-1"-yl)cyclohexyl](pyrrolidin-1-yl)]methanone,

71. 8-Chloro-1-[trans-4-(trifluoromethyl)cyclohexyl]-4H-[1,24]triazolo[4,3-a][1 Ibenzazepin-5(6H)-one,

72. 8-Chloro-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepine -5-ol,

73. (cis)-8-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2.5"-[1,2,4]triazolo[4,3-a] [1]benzazepin]-1"-11)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one,

74. —8-Chloro-S-methoxy-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a ][1]benzazepine,

75. (trans)-8-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,24]triazolo[4,3-a][ 1]benzazepin]-1"-11)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one,

76. N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]benzazepin-5-yl)-N-methylmethanesulfonamide,

77. (5S)-8-chloro-N-ethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4] triazolo[4,3-a][1 |benzazepine-5-amine,

78. (5S)-8-chloro-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4] triazolo[4,3-a][1 |benzazepine-5-amine,

79. 8'-Chloro-1"-[1-(pyrimidin-2-yl)azetidin-3-11])-4'H,6'H-spiro[1,3-dioxolane-2,5'-[ 1,2,4]triazolo[4,3-a][1]|benzazepine],

80. N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazole [4,3-a][1]benzazepin-5-11)-4-fluorobenzamide,

64 / 323

81. &-bromo-1"-[trans-4-(trifluoromethyl)cyclohexyl]|-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4 ]triazolo[4,3-a][1]benzazepine],

82. 5-(Propan-2-ylamino)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4] trifluoroacetate triazolo[4,3-a][1]benzazepin-8-carbonitrile,

83. (55)-8-chloro-N-(4-fluorobenzyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1, 2 A4]triazolo[4,3-a][1]benzazepine-5-amine,

84. 1º-[trans-4-(trifluoromethyl)cyclohexyl]-4'º H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4, 3-a][1]|benzazepine]-8'-carbonitrile,

85. [trans-4-(8'-bromo-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2A]triazolo[4,3-a][1] |benzazepin]-1"-yl)cyclohexyl](piperidin-1-yl)]|methanone,

86. — trans-4-(8-bromo-5-OxO-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1 Ibenzazepin-1-yl)cyclo -methyl hexanecarboxylate,

87. 8-bromo-1-[trans-4-(piperidin-1I-ylcarbonyl)cyclohexyl]-4H-[1,2,A]triazolo[4,3-a][1]benzazepin-S(6H )-one,

88. 8'-Chloro-1"-[trans-4-(trifluoromethyl)cyclohexyl]|-4'H,6'H-spiro[1,3-dioxane-2,5'-[1,2, 4]triazolo[4,3-a][1]benzazepine],

89. 1'-[trans-4-(piperidin-1-ylcarbonyl)cyclohexyl]|-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4 ]triazolo[4,3-a][1]benzazepin]-8'-carbonitrile,

90. —&-chloro-11'-[trans-4-(pyridin-2-yloxy)cyclohexyl |-4'H,6'H-spiro[1,3-dioxane-2,5'-[1] ,2,4]triazolo[4,3-a][1]|benzazepine],

91. 8-bromo-1-[trans-4-(trifluoromethyl)cyclohexyl]β-4H-[1,24]triazolo[4,3-a][1Ibenzazepin-5(6H)-one,

92. [trans-4-(8-bromo-5-hydroxy-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1Ibenzazepin-1-yl)cyclo- hexyl ]|(piperidin-1-yl)]methanone,

93. 8-bromo-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a][1]benzazepin- 5-hol,

65 /323

94. 1'-(1,4'-bipiperidin-1"-11)-8"-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2, 4]triazolo[4,3-a][1]benzazepine],

95. [1-(1,4'-bipiperidin-1"'-yl)-8-chloro-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1 ]Ibenzazepin-5-yl | tert-butyl carbamate,

96. 8-Fluoro-1'-[trans-4-(pyridin-2-yloxy)cyclohexyl |-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1, 2,4]triazolo[4,3-a][1]benzazepine],

97. (55)-8-chloro-N-(4-fluorobenzyl)-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H -[1,2,A4]triazolo[4,3-a][1]benzazepin-5-amine,

98. — N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4] triazolo[4,3-a][1 |benzazepin-5-yl |prop-2-enamide,

99. (5R)-8-chloro-N-ethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A] triazolo[4,3-a][1]benzazepin-5-amine,

100. (5R)-8-chloro-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A] triazolo[4,3-a][1]benzazepin-5-amine,

101. (5R)-8-chloro-N,N-dimethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4 ]triazolo[4,3-a][1 |benzazepin-5-amine,

102. 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4H-[1,24]triazolo[4,3-a][1Ibenzazepin-5(6H)-one,

103. — (55)-8-chloro-5-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4 ]triazolo[4,3-a][1]benzazepine,

104. (5R)-8-chloro-5-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4] triazolo[4,3-a][1 |benzazepine,

105. 8-Chloro-5-(propan-2-yloxy)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1.2A ]triazolo[4,3-a][1 Ibenzazepine,

106. 8"-chloro-1'-[trans-4-(pyridin-2-yloxy)cyclohexyl]|-4'H,6'H-spiro[1,3-dioxepane-2,5'-[ 1,2,4]triazolo[4,3-a][1]benzazepine],

107. 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

66 / 323 [1,2 4]triazolo[4,3-a][1]Ibenzazepin-5-ol,

108. [trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,24]triazolo[4,3-a][1] ]benzazepin]-1"-yl)cyclohexyl |(morpholin-4-yl)]methanone

109. “S-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a ][1]benzazepine,

110. 8-Fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]|-4H-[1,24]triazolo[4,3-a][1Ibenzazepin-5(6H) -one,

111. — 8-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a ][1]benzazepin-5-ol,

112. —tert-butyl — (8-chloro-1-[trans-4-(morpholin-4-yl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1 |benzazepin-5-yl |carbamate of,

113. 8-Chloro-1-[trans-4-(morpholin-4-yl)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a][ 1 |benzazepin-5-amine,

114. 8-Chloro-1-[trans-4-(morpholin-4-yl)cyclohexyl]-N-(propan-2-yl)-5,6-dihydro-4H-[1.2A ]triazolo[4,3-a][1 Ibenzazepin-5-amine,

115. (5r,8r)-8-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2.5"-[1,24]triazolo[4,3-a ][1]benzazepin]-1"-11)-2-(propan-2-yl)-2-azaspiro[4.5]decan-1-one,

116. (5r,8r)-8-(8-chloro-5-hydroxy-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1]|benzazepin-1 -i1)-2-(propan-2-yl)-2-azaspiro[4.5]decan-1-one,

117. (5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5-(pyrrolidin-1-11)-5,6-dihydro-4H-[ 1,2,4]triazolo[4,3-a][1]benzazepine,

118. N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]benzazepin-5-yl)-2,2-dimethylpropanamide,

119. N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]benzazepin-5-yl)cyclopropanecarboxamide,

67 /323

120. N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]benzazepin-5-yl)-2-methylpropanamide,

121. N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1 Ibenzazepin-5-yl)cyclobutanecarboxamide,

122. (55)-8-chloro-5-(morpholin-4-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A4]triazolo[4,3-a][1 Ibenzazepine,

123. N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]Ibenzazepin-5-yl)-2,2-dimethylpropanamide,

124. N-((5SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazole [4,3-a][1]benzazepin-5-11)-2-methylpropanamide,

125. N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]benzazepin-5-yl)cyclobutanecarboxamide,

126. N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]benzazepin-5-yl Icyclopropanecarboxamide,

127. (55)-8-chloro-5-(piperidin-1-11)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A4]triazolo[4,3-a][1 Ibenzazepine,

128. (5S)-N-(butan-2-yl)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 4]triazolo[4,3-a][1 Ibenzazepin-5-amine,

129. (5s,85)-8-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2.5"-[1,24]triazolo[4,3-a ][1 Ibenzazepin]-1"-11)-2-(propan-2-yl)-2-azaspiro[4.5]decan-1-one,

130. S8-chloro-S5-methoxy-1-[trans-4-(morpholin-4-yl)cyclohexyl]-

68 /323 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine,

131. — 8-Chloro-5-ethoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4 ,3-a][1]benzazepine,

132. — (5R)-8-chloro-S-methoxy-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4 ,3-a][1]benzazepine,

133. (55)-8-chloro-5-methoxy-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1]benzazepine,

134. 8-Fluoro-5-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4]triazolo[4,3 -a][1 Ibenzazepine,

135. 8-Chloro-N-(propan-2-yl)-1-[1-(pyridin-2-yl)piperidin-4-yl]-5,6-dihydro-4H-[1,2, 4]triazolo[4,3-a][1 |benzazepin-5-amine,

136. 2-((8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3 -a][1]benzazepin-5-yl Joxy)ethanol,

137. (55)-8-chloro-N N-diethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A ]triazolo[4,3-a][1]benzazepin-5-amine,

138. 8-Chloro-N-methyl-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A4]triazolo[4,3-a][1 |benzazepin-5-amine,

139. (8-Chloro-1-[4-(3-chloropyridin-2-1yl)piperazin-1-yl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3] -a][1 |benzazepin-5-yl |tert-butyl carbamate,

140. 4-(8-Chloro-S-methoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-yl)piperidine-1 - tert-butyl carboxylate,

141. N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazole [4,3-a][1]benzazepin-5-yl |-D-valinamide,

142. (1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1 Ibenzazepin- tert-butyl 5-yl |) carbamate,

143. (8-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a] [1 Ibenzazepin-5-yl] tert-butyl carbamate,

144. 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-

69 /323 [1,2 4]triazolo[4,3-a][1]|benzazepin-5-amine,

145. 8-Fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a] [1]|benzazepin-5-amine,

146. 8-Fluoro-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2, A4]triazolo[4,3-a][1]benzazepin-5-amine,

147. 8-Fluoro-N,N-dimethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1]benzazepin-5-amine,

148. N,N-dimethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3- a][1]benzazepin-5-amine,

149. 8'-Fluoro-1"-[trans-4-(trifluoromethyl)cyclohexyl]|-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2, 4]triazolo[4,3-a][1]benzazepine],

150. — N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazole [4,3-a][1]benzazepin-5-amine,

151. N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazole [4,3-a][1]benzazepin-5-yl Htetrahydro-2H-pyran-4-carboxamide,

152. N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]benzazepin-5-yl |-2-methylbutanamide,

153. N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]benzazepin-5-yl 1-Nº,Nº-dimethyl-g-alaninamide,

154. (5S)-8-chloro-N-cyclopentyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4]triazole [4,3-a][1 |benzazepin-5-amine,

155. 8'-Chloro-1"-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1-11)-4'H,6'H-spiro[1,3-dioxolane -2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine],

156. 8-Chloro-1-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1"-yl)-4H-[1,2,A]triazolo[4,3- a][1]benzazepin-S(6H)-one,

157. 8'-Chloro-1'-[4-(pyridin-2-yloxy)piperidin-1-11]-4'H,6'H-

spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine],

158. N-((55S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazole [4,3-a][1]benzazepin-5-yl)-2,2-dimethylbutanamide,

159. N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]benzazepin-5-yl)-2-hydroxy-2-methylpropanamide,

160. (55)-8-chloro-N-ethyl-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1, 2 A4]triazolo[4,3-a][1 Ibenzazepin-5-amine,

161. (55)-8-chloro-N-(2-methylpropyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1, 2,A]triazolo[4,3-a][1 Ibenzazepin-5-amine,

162. 8-Chloro-1'-[trans-4-(morpholin-4-yl)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1, 2,4]triazolo[4,3-a][1]benzazepine] hydrochloride of,

163. 8-Chloro-N,N-dimethyl-1-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1"-11)-5,6-dihydro-4H- [1,2,4]triazolo[4,3-a][1]benzazepin-5-amine,

164. 8'-Chloro-1'-[4-(3-chloropyridin-2-yl)piperazin-1-11])-4'H,6'H-spiro[1,3-dioxolane-2,5' -[1,2,4]triazolo[4,3-a][1]benzazepine],

165. (55)-8-chloro-N-(2,2-dimethylpropyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A4]triazolo[4,3-a][1 |benzazepin-5-amine,

166. [trans-4-(8-chloro-5-methoxy-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1Ibenzazepin-1-yl)cyclo- hexyl |(4-methylpiperazin-1-yl)]methanone,

167. (5R)-8-chloro-5-(morpholin-4-11)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A]triazolo[4,3-a][1 Ibenzazepine,

168. N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazole [4,3-a][1]benzazepin-5-yl Jacetamide,

169. N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazole [4,3-a][1]benzazepin-5-yl)-2-hydroxy-2-methylpropanamide,

170. 8-Chloro-5-methoxy-1-[1-(tetrahydro-2H-pyran-4-yl)piperidin-4-11]-5,6-dihydro-4H-[1,2, A4]triazolo[4,3-a][1]benzazepine,

171. 8'-Chloro-1'-[4-(pyridin-2-yl)piperazin-1-11)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1 ,2,4]triazolo[4,3-a][1]benzazepine],

172. 8-Chloro-1-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1"-11)-5,6-dihydro-4H-[1,24 ]triazolo[4,3-a][1 Ibenzazepin-5-ol,

173. 8-Chloro-1-[4-(3-chloropyridin-2-yl)piperidin-1-11]-5,6-dihydro-4H-[1,24]triazolo[4,3-a ][1]Ibenzazepin-5-ol,

174. (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5-(pyrrolidin-1-11)-5,6-dihydro-4H-[ 1,2 4]triazolo[4,3-a][1]benzazepine,

175. 8-Chloro-5-methoxy-1-([1-[(3S)-tetrahydrofuran-3-ylpiperidin-4-11)-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepine,

176. (5R)-8-fluoro-5-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4] triazolo[4,3-a][1]benzazepine,

177. (55)-8-fluoro-S-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4] triazolo[4,3-a][1]benzazepine,

178. 8-Chloro-5-methoxy-1-(1-[(3R)-tetrahydrofuran-3-ylpiperidin-4-11)-5,6-dihydro-4H-[1,2 A4]triazolo[4 ,3-a][1 |benzazepine,

179. N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1-benzazepin-5-yl 1-Nº,Nº-dimethyl-g-alaninamide,

180. N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4]triazolo[ 4,3-a][1]benzazepin-5-yl)tetrahydro-2H-pyran-4-carboxamide,

181. 8-Chloro-1-[4-(pyridin-2-yloxy)piperidin-1-11]-5,6-dihydro-4H-[1,2A4]triazolo[4,3-a][ 1]benzazepin-5-ol,

182. 8-Chloro-S-methoxy-1-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1]benzazepine,

183. 8-Chloro-5-methoxy-1-[cis-4-(4-methylpiperazin-1-yl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1]benzazepine,

184. 8-Chloro-5S-methoxy-1-[1-(pyridin-3-ylmethyl)pyrrolidin-3-11]-5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1]benzazepine,

185. 8-Chloro-S5-methoxy-1-[1-(pyridin-2-ylmethylpyrrolidin-3-yl]-5,6-dihydro-4H-[1,24]triazolo[4,3-a ][1 ]|benzazepine,

186. N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24]triazolo[ 4,3-a][1 Ibenzazepin-5-11)-2-cyanoacetamide,

187. [3-(8-chloro-5-methoxy-5,6-dihydro-4H-[1,2,A]triazolo[4,3-al[1]benzazepin-1-yl)pyrrolidin-1 -yl](pyridin-3-yl)]methanone,

188. 8'-Chloro-1"-(1-[(3R)-tetrahydrofuran-3-yl]piperidin-4-11)-4'H,6'H-spiro[1,3-dioxolane-2,5 '-[1,2,4]triazolo[4,3-a][1]benzazepine],

189. [3-(8-chloro-5-methoxy-5,6-dihydro-4H-[1,2A]triazolo[4,3-al[1]benzazepin-1-yl)pyrrolidin-1- 1] (pyridin-2-yl)]Imethanone,

190. trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2.5"-[1,24]triazolo[4,3-a][1] benzazepin]-1"-11)-N,N-dimethylcyclohexanamine,

191. 8-Chloro-5-methoxy-1-(1'H,3H-spiro[2-benzofuran-1,4"-piperidin]-1'-11)-5,6-dihydro-4H-[ 1,2 4]triazolo[4,3-a][1]benzazepine,

192. 8-Chloro-1-[4-(3-chloropyridin-2-yl)piperazin-1-yl]-5-methoxy-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1]|benzazepine,

193. N-[trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,24]triazolo[4,3-a] [1 Ibenzazepin]-1'"-yl)cyclohexyl Ipyridin-2-amine

194. N'-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4]triazole [4,3-a][1]benzazepin-5-yl)-N,N-dimethylethane-1,2-diamine,

195. 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a][ 1]benzazepin-5-yl acetate,

196. 2-(1(5SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4] triazolo[4,3-a][1]benzazepin-5-yl]yamino)ethanol,

197. 8-Chloro-5S-methoxy-1-[4-(pyridin-2-yloxy)piperidin-1-11]-5,6-dihydro-4H-[1,2,A]triazolo[4, 3-a][1]benzazepine,

198. 8"-chloro-1'-(trans-4-methoxy-4-methylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2, 4]triazolo[4,3-a][1]benzazepine],

199. — (5S)-8-chloro-N-(cyclopropylmethyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4]triazolo[4,3-a][1 |benzazepin-5-amine,

200. N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1|benzazepin-5-yl)-1-methylpiperidine-4-carboxamide,

201. N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazole [4,3-a][1]benzazepin-5-11)-2,2,2-trifluoroacetamide,

202. 8-Chloro-5-(2-methoxyethoxy)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazole [4,3-a][1]benzazepine,

203. 8-Chloro-1-(4-methoxy-4-methylcyclohexyl)-N-(propan-2-yl)-5,6-dihydro-4H-[1,2,A4]triazolo[4 ,3-a][1]|benzazepin-5-amine,

204. 8-Chloro-1'-(trans-4-methoxy-4-methylcyclohexyl)-4'H,6'H-spiro[1,3-dioxane-2,5'-[1,2,4 ]triazolo[4,3-a][1]benzazepine],

205. 8'-Chloro-1"-(cis-4-methoxy-4-methylcyclohexyl)-4'H,6'H-spiro[1,3-dioxane-2,5'-[1,2, 4]triazolo[4,3-a][1]|benzazepine],

206. 8-Chloro-5-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1 Ibenzazepine,

207. S8-Chloro-5-[2-(methylsulfonyl)ethoxy]-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A]triazolo[4,3-a][1 Ibenzazepine,

208. 8-Chloro-N-hydroxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4H-[1,2A4]triazolo[4,3-a][1]benzazepin- S(6H)-imine,

209. (55)-8-chloro-N-methyl-N-(prop-2-yn-1-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6 -dihydro-4H-[1,2,A4]triazolo[4,3-a][1]benzazepin-5-amine,

210. N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]benzazepin-5-yl)-3,3-difluorocyclobutanecarboxamide,

211. 8-Chloro-5-(prop-2-yn-1-yloxy)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A4]triazolo[4,3-a][1]benzazepine,

212. 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a] [1]benzazepin-5-yl 4 A4-difluorocyclohexanecarboxylate,

213. 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a][ 1]benzazepin-5-yl 3,3-difluorocyclobutane carboxylate,

214. N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]benzazepin-5-yl)-4,4-difluorocyclohexanecarboxamide,

215. 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a] [1]benzazepin-5-yl cyanoacetate,

216. 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a] [1 |benzazepin-5-yl N N-dimethylglycinate,

217. N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]Ibenzazepin-5-yl)-2,2,2-trifluoroacetamide,

218. 1-[cis-4-(8-chloro-S-methoxy-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1 Ibenzazepin-1-yl) cyclohexyl Ipyrrolidin-2-one,

219. 1-[trans-4-(8-chloro-5-methoxy-5,6-dihydro-4H-[1,2A]triazolo[4,3-a][1]benzazepin-1-yl )cyclohexyl]pyrrolidin-2-one,

220. N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-

5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl)-3,3-difluorocyclobutanecarboxamide,

221. N-((5R)-8-chloro-1-[trans-4-(pyridin-2-1loxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazole [4,3-a][1]benzazepin-5-yl)-4,4-difluorocyclohexanecarboxamide,

222. 8-Chloro-S5-methoxy-1-[cis-4-methoxy-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1]benzazepine,

223. 8-Chloro-5-methoxy-1-[trans-4-methoxy-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2 A4]triazolo[4,3 - a][1]benzazepine,

224. (5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-N-(2,2,2-trifluoroethyl)-5,6-dihydro-4H -[1,2,A]triazolo[4,3-a][1]benzazepin-5-amine,

225. N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazole [4,3-a][1]benzazepin-5-11)-3-methyloxetane-3-carboxamide,

226. N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]benzazepin-5-yl |-3-methyloxetane-3-carboxamide,

227. trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2.5"-[1,24]triazolo[4,3-a][1 Ibenzazepin ]-1"-yl)-N-(4-methoxybenzyl)cyclohexanamine,

228. [2-(1(SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24] triazolo[4,3-a][1]|benzazepin-5-11)jamino)ethyl|tert-butyl carbamate,

229. 8'-Chloro-1'-(trans-4-ethoxy-4-ethylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2, 4]triazolo[4,3-a][1]|benzazepine],

230. trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2 A]triazolo[4,3-a][1] benzazepin]-1"-yl)-N-(4-methoxybenzyl)-N-methylcyclo-

hexanamine,

231. 8'-Chloro-1'-[1-(pyridin-3-ylmethyl)pyrrolidin-3-11)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1 ,2,4]triazolo[4,3-a][1]benzazepine],

232. 8-Chloro-5S-methoxy-1-[4-(pyridin-2-yl)piperazin-1-11]1-5,6-dihydro-4H-[1,2,4]triazolo[4 ,3-a][1]benzazepine,

233. 8-Chloro-1-(trans-4-ethyl-4-methoxycyclohexyl)-N N-dimethyl-5,6-dihydro-4H-[1,2,A4]triazolo[4,3- a][1 |benzazepin-5-amine,

234. 8-Chloro-1-(trans-4-ethoxy-4-methylcyclohexyl)-N,N-dimethyl-5,6-dihydro-4H-[1,2A4]triazolo[4,3- a][1 Ibenzazepin-5-amine,

235. 8'-Chloro-1"-[trans-4-methoxy-4-(trifluoromethyl)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1 ,2,4]triazolo[4,3-a][1 |benzazepine],

236. 8'-Chloro-1"-[cis-4-methox1-4-(trifluoromethyl)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1 ,2,4]triazolo[4,3-a][1]benzazepine],

237. 8'-Chloro-1"-(trans-4-ethoxy-4-methylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2, 4]triazolo[4,3-a][1]benzazepine],

238. 8'-Chloro-1"-(trans-4-ethoxy-4-propylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2, 4]triazolo[4,3-a][1]benzazepine],

239. “8'-Chloro-1'-[1-(pyridin-2-ylmethyl)pyrrolidin-3-11])-4'H,6'H-spiro[1,3-dioxolane-2,5'- [1,2,4]triazolo[4,3-a][1]benzazepine],

240. 8'-Chloro-1'-(cis-4-ethyl-4-methoxycyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2, 4]triazolo[4,3-a][1]benzazepine],

241. 8'-Chloro-1"-(trans-4-ethyl-4-methoxycyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2, 4]triazolo[4,3-a][1]benzazepine],

242. r-chloro-1'-(trans-4-methoxy-4-propylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4 ]triazolo[4,3-a][1]benzazepine],

243. 8'-Chloro-1'-(cis-4-methoxy-4-propylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2, 4]triazolo[4,3-a][1]|benzazepine],

244. 8-Chloro-1-(trans-4-ethoxy-4-ethylcyclohexyl)-N-(propan-2-11)-5,6-dihydro-4H-[1,2 A4]triazolo[ 4,3-a][1]benzazepin-5-amine,

7Q7/323

245. —8-Chloro-1-(trans-4-ethoxy-4-ethylcyclohexyl)-N,N-dimethyl-5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1]|benzazepin-5-amine,

246. 8'-Chloro-1'-[(3R)-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl]-4'H,6'H-spiro[1,3-dioxolane-2,5 '-[1,2,4]triazolo[4,3-a][1]benzazepine],

247. &-chloro-S-methoxy-1-[(3R)-1-(pyridin-3-ylmethyl)pyrrolidin-3-11]1-5,6-dihydro-4H-[1,2,4 ]triazolo[4,3-a][1 |benzazepine,

248. &-chloro-S-methoxy-1-[(3R)-1-(pyridin-2-ylmethyl)pyrrolidin-3-11]1-5,6-dihydro-4H-[1,2,4 ]triazolo[4,3-a][1 |benzazepine,

249. 8'-Chloro-1"-[(3S)-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-4'H,6'H-spiro[1,3-dioxolane-2,5 '-[1,2,4]triazolo[4,3-a][1]|benzazepine],

250. 8'-Chloro-1"-[(3R)-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-4'H,6'H-spiro[1,3-dioxolane-2,5 '-[1,2,4]triazolo[4,3-a][1]benzazepine],

251. 8-Chloro-S-methoxy-1-[(3S)-1-(pyridin-3-ylmethyl)pyrrolidin-3-11])-5,6-dihydro-4H-[1,2 A4] triazolo[4,3-a][1]benzazepine,

252. 8'-Chloro-1"-[(3S)-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl]-4'H,6'H-spiro[1,3-dioxolane-2,5 '-[1,2,4]triazolo[4,3-a][1]benzazepine] and

253. 8-Chloro-S-methoxy-1-[(3S)-1-(pyridin-2-ylmethyl)pyrrolidin-3-111-5,6-dihydro-4H-[1,24]triazolo[ 4,3-a][1]benzazepine.

[00275] The present invention also relates to the synthesis of compounds of general formula (1). Accordingly, compounds of formula (1) of the present invention can be prepared by one of the following methods:

[00276] Insofar as, in the compound of formula (1), R? is hydrogen, Rº is -NHBoc or -OSi(CH;)>-t-butyl group and ring A is a cycloalkyl or a saturated 4- to 7-membered heterocycle containing 1 N, in which ring A is fixed via the nitrogen in the ring to Y, compounds of general formula (1) of the present invention are prepared by reacting compounds of general formula (II) or

OO (1)

- wherein ring B and Y are as defined above for general formula (1) and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the nitrogen in the ring to Y - and compounds of general formula mM

N (1) - where R' is as defined above for the general formula (1), Rº is hydrogen, R? is -NHBoc or -OSi(CH;3)2-t-butyl group - or the compounds of general formula (IV) and Na (V) - wherein R' is as defined above for formula (1), Rº is hydrogen , R? is -NHBoc or -OSi(CH;),-t-butyl group.

[00277] The procedure is shown in detail in Phase 1 Da. a x EraAçõ. ce) " cS o os' TOR, É ; n ; LO (11) (11) (IV) (I-a) " Scheme |

[00278] In step a) of Scheme 1 the acid hydrazide of general formula (II) is reacted with the benzazepine-thione of general formula (III) or the methylsulfanyl-benzazepine derivatives of general formula (IV). The reaction is preferably carried out in a suitable solvent, at the boiling point of the solvent, with a required reaction time of 4 to 150 hours. Suitable solvents include xylene, n-butanol, 1,4-dioxane.

[00279] Preferred embodiments are, for example, as follows: i) reaction of (II) and (II) in xylene at 140°C for 20 to 150 hours, or

11) reaction of (II) and (III) in n-butanol at 110°C for 20 to 50 hours, or iii) reaction of (II) and (III) in 1,4-dioxane at 110°C for 4 hours, or 1v ) reaction of (II) and (IV) in xylene in the presence of catalytic hydrogen chloride at 140°C for 4 to 20 hours, or v) reaction of (II) and (IV) in 1,4-dioxane in the presence of chloride catalytic hydrogen at 110°C for 4 to 20 hours.

[00280] Synthesis of the acid hydrazides of general formula (II) can be carried out in several ways (Scheme 2): - OAK NH—NH, OO 2 Er" V) (1) O) to OrOC 2 OrOs (Vl) ( VI) Scheme 2

[00281] In step a) of Scheme 2, the carboxylic acid esters of general formula (V) are reacted with hydrazine hydrate in an appropriate alcohol at the boiling point of the solvent to obtain the acid hydrazides of general formula (II) or, in step c), the carboxylic acids of general formula (VD) are reacted with -fert-butyl carbazate and the protecting group of the obtained protected carboxylic acid hydrazide derivative of general formula (VII) is removed with acid ( step d)).

[00282] Preferred embodiments are, for example, as follows: step a) methanol or ethanol, hydrazine hydrate, reflux temperature, 4 to 50 hours; step b) methanol, thionyl chloride, 0 at 25°C, 4 to 24 hours; step c) tert-butyl carbazate, N,N-dimethylformamide, N,N-diisopropylethylamine, N-(3-dimethylaminopropyl)-N'"-ethylcarbodi-

80 / 323 imide, 1-hydroxybenzotriazole hydrate, room temperature, 4 to 20 hours; step d) hydrogen chloride in ethyl acetate, room temperature, 4 to 20 hours.

[00283] The carboxylic acid esters of general formula (V) and the carboxylic acids of general formula (VI) are either commercially available or can be prepared according to the methods described in the Examples.

[00284] Insofar as, in compounds of general formula (1), R' is as defined above for general formula (1), R? is hydrogen, R? is -NHBoc, the benzazepine-thione derivatives of general formula (III) and methylsulfanyl benzazepine derivatives of general formula (IV) can be prepared according to the following procedures:

[00285] The key intermediate benzazepine derivative of general formula (XIII) can be prepared according to the following Method A (Scheme 3) and Method B (Scheme 4): Method A: and NO, is No, SE — ST alley OI Im (DO) co jo 4 o Nz NO? E Ee of R SS ij cooH Í cooH Eu XI) or Scheme 3

[00286] In step a) of Scheme 3, amino group of the amino acid derivative of general formula (VIII), which is commercially available or can be prepared according to the methods described in the Examples, - wherein R! is as defined above for the general formula (1) - is protected by a tert-butoxycarbonyl protecting group, then with the thus obtained protected amino acid derivative (IX) - wherein R' is as defined above for the general formula (1) ) — the Arndt-Eistert reaction (Arndt, F., Eisert, B. Chem Ber 1935, 68(1):200-208) is carried out in two steps: first, the acid chloride prepared in situ of the compound of formula (IX) is reacted with diazomethane (steps b) and c)) to give the diazo compound of general formula (X) - wherein R' is as defined above for general formula (1) - which in step d) is converted in the amino acid derivative of general formula (XI) in the presence of a silver salt - wherein R' is as defined above for general formula (1). The nitro group of the latter is reduced (step e)) to obtain the amine of general formula (XII) - where R' is as defined above for general formula (1) - which is ring-closed by a reactant capable of forming an amide bond (step f)) to obtain the benzazepine derivative of general formula (XIII) - wherein R' is as defined above for general formula (1).

[00287] Preferred embodiments are, for example, as follows: step a) di-tert-butyl dicarbonate, 1,4-dioxane, aqueous sodium hydroxide solution, room temperature, 4 to 20 hours; step b) isobutyl chloroformate, triethylamine, diethyl ether, -30°C, 15 to 45 minutes; step c) diazomethane solution in ether, -30°C to 0°C, 1 to 3 hours; step d) silver benzoate, 1,4-dioxane, water, room temperature, 4 to 20 hours; step e) i) sodium borohydride, methanol, nickel chloride, room temperature, 4 to 20 hours, or ii) hydrogenation in the presence of Pt/C catalyst, toluene, room temperature, 4 to 20 hours; step E) N N-dimethylformamide, N,N-diisopropylethylamine, N-(3-dimethylaminopropyl)-N"-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole hydrate, room temperature, 4 to 20 hours Method B: Nut NO, oa NO, No cooM a) ANN COOAK c) 2 >cooak Tr om o — o —=— NH R Rº Rº Rº (XIV) (XV) (XV) (XVI [ o NH> NO2 NO? NHBOc NHBoc o color 'COOAIK 'COOAIKk no RR Rº > 0X) XI) XVI lo H o NHz NO? CO D OT > OT Rn cooH CcooH NHBoc ;

R R (XI) (XI) (x) Scheme 4

[00288] In step a) of Scheme 4, the derivative phenyl acetic acid of general formula (XIV), which is commercially available or can be prepared according to the methods described in the Examples - wherein R' is as defined above for the general formula (1) - is reacted with Meldrum acid to obtain the compound of general formula (XV) - wherein R' is as defined above for general formula (1) - which is reacted with an appropriate alcohol (step b )) to obtain the keto-ester derivative of general formula (XVI) - wherein R' is as defined above for general formula (1) and Alk is C1,alkyl group -, the latter is converted with the compound of formula (XVII) by adding ammonium acetate (step c)) - where R! is as defined above for general formula (1) and Alk is C1,alkyl - group, which is reduced in step d) and the resulting amino compound of general formula (XVIII) is obtained - wherein R' is as defined above for the general formula (1) and Alk is C1 alkyl group — the amino group is protected with tert-butoxycarbonyl group (step e)) to obtain the compound of general formula (XIX) — wherein R' is as defined above for The

83 /323 general formula (1) and Alk is C1,alkyl group. The nitro group of the latter is reduced in step f) and the thus obtained compound of general formula (XX) - wherein R' is as defined above for general formula (1) and AIk is C1,alkyl group - is ring-closed in the presence of an appropriate base (step g)) to obtain the compound of formula (XIII) - wherein R' is as defined above for general formula (1).

[00289] The compound of formula (XIII) can also be prepared by hydrolysis of the compound of general formula (XIX) - wherein R' is as defined above for general formula (1) and Alk is C1,4 alkyl group - in the presence of an appropriate base (step h)) and the resulting compound of formula (XI) - wherein R' is as defined above for general formula (1) — is converted to the compound of general formula (XIII) via the steps shown in Method A (step 1) of Method B is identical to step e) of Method A and step j) of Method B is identical to step f) of Method A).

[00290] Preferred embodiments are, for example, as follows: step a) Meldrum's acid, acetonitrile, N,N-diisopropylethylamine, pivaloyl chloride, 4-dimethylaminopyridine, 20 to 50°C, 4 to 6 hours; step b) methanol, toluene, 110 to 120°C, 1 to 6 hours; step c) ammonium acetate, methanol, room temperature, 20 to 75 hours or 60°C for 5 to 20 hours; step d) sodium triacetoxyborohydride, acetic acid, room temperature, 2 to 48 hours; step e) sodium bicarbonate, methanol, di-tert-butyl dicarbonate, 5 to 25°C; 1 to 20 hours; step f) i) hydrogenation in the presence of Pt/C catalyst, toluene, room temperature, 4 to 20 hours, or ii) hydrogenation in the presence of Pd/C catalyst, methanol, room temperature, 4 to 20 hours;

step g) i) methanol, sodium methoxide, room temperature, 2 to 20 hours, or ii) tetrahydrofuran, potassium tert-butoxide, 0 to 25°C, 2 to 20 hours; step h) lithium hydroxide, methanol, water, tetrahydrofuran, room temperature, 4 to 20 hours.

[00291] The benzazepine-thione derivatives of general formula (III) and methylsulfanylbenzazepine derivatives of general formula (IV) are prepared (Scheme 5) by reaction of a compound of general formula (XIII) obtained by Method A or B Ho Hs SMe Cf > E oç NHBoc' NHBoc & NHBoc XI (IIt-a) (IV-a) Scheme 5 - where R' is as defined above for general formula (1) - with Lawesson's reagent (step a) ), then the thus obtained benzazepine-thione of general formula (IlI-a) - wherein R! is as defined above for general formula (1) - is methylated (step b)) to give the methylsulfanyl-benzazepine derivative of general formula (IV-a) - wherein R' is as defined above for general formula (1) ).

[00292] Preferred embodiments are, for example, as follows: step a) i) Lawesson's reagent, pyridine, 90 to 120°C, 4 to 20 hours, or 1) Lawesson's reagent, tetrahydrofuran, room temperature, 4 to 20 hours; step b) iodomethane, potassium carbonate, acetone, room temperature, 4 to 24 hours.

[00293] Compounds of general formula (I-b) are prepared by reacting a compound of general formula (III-a) or a compound of general formula

85/323 (IV-a) with a compound of general formula (II) (Scheme 6)" a PS (1) (IIII-a) (IV-a) (Oe Scheme 6 - wherein ring B, Y, R ' is as defined above for the general formula (1), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is attached via the nitrogen in the ring to Y.

[00294] Preferred embodiments of step a) of Scheme 6 are, for example, as follows: i) reaction of (II) and (IlI-a) in xylene at 140°C for 20 to 150 hours, or ii) reaction of (II) ) and (II-a) in n-butanol at 110°C for 20 to 50 hours, or iii) reaction of (II) and (ITI-a) in 1,4-dioxane at 110°C for 4 hours, or iv) reaction of (II) and (IV-a) in xylene in the presence of catalytic hydrogen chloride at 140°C for 4 to 20 hours, or v) reaction of (II) and (IV-a) in 1,4-dioxane in the presence of catalytic hydrogen chloride at 110°C for 4 to 20 hours.

[00295] The compounds of general formula (Ib) thus obtained, if desired, can also be converted into another compound of general formula (D) by known methods with the introduction of new substituents and/or with the modification, removal of existing substituents and/or with salt formation and/or with release of the base from the salts and/or with the preparation of the enantiomers from racemic mixtures. This is illustrated in detail in Scheme 7:

86 / 323 and E es am ” | O. aa) of : | | NO ES oO, at and wed and AA Diagram 7

[00296] The protecting group of compound of general formula (Ib) can be removed in an appropriate acidic medium (step a)), the compounds of general formula (Ic) thus obtained - in which ring B, Y, R' are as defined above for general formula (1), ring A is a cycloalkyl or saturated 4- to 7-membered heterocycle containing 1 N, in which ring A is fixed via the nitrogen in the ring to Y - may be sulfonylated or acylated (step b)) and compounds of formula (Id) - wherein R is C(O)R? or S(OO:)R"* as defined in general formula (1) in the meaning of Rº or Rº -, can be optionally alkylated (step c)) thus compounds of general formula (Ie) are obtained. After alkylation (step d)) of compounds of general formula (I-b) followed by deprotection (step g)) gives the mono-alkyl derivatives of general formula (Ig) which can be converted with further alkylation (step h)) to derivatives di-alkyl of general formula (Ih). The two alkyl groups may be different and/or identical. Monoalkyl or Cy' derivatives of general formula (Ig) may also be prepared by reductive amination (step e)) from amine derivative of general formula (Ic) Dialkyl derivatives of general formula (Ih) can also be prepared from amine derivatives of general formula (Ic) by reductive amination (step f)) if the two alkyl groups are identical. compounds of general formula (I-wW) — where

87 /323 Rº and Rº taken together with the N to which they are attached form a heterocycle - can also be obtained from compounds of general formula (Ic) (step k)) using an appropriate dihalogen compound in the presence of a base. Pure enantiomers can be obtained from chiral HPLC or resolution of compounds of general formula (I-c) from which acyl and/or alkyl derivatives can also be prepared. When the compound of general formula (I-c) is an enantiomer pure, the chiral compound of general formula (I-b) is prepared to produce monoalkyl plus chiral derivatives. In the general formulas (Ie), (ID), (Ig) and (Ih), the term "alkyl" is Cx. 1 optionally substituted alkyl as defined in general formula (1) in the meaning of R* or R* and in the general formula (Ig) Cy' is as defined for formula (1).

[00297] Preferred embodiments are, for example, as follows: step a) and g) hydrogen chloride in ethyl acetate, room temperature, 1 to 20 hours step b) i) sulfonyl chloride, pyridine, room temperature, 4 to 20 hours, or 11) sulfonyl chloride, dichloromethane, triethylamine or N,N-diisopropylethylamine, room temperature, 4 to 20 hours, or 111) acyl chloride, pyridine, at room temperature for 4 to 20 hours, or iv) acyl chloride, dichloromethane, triethylamine or N,N-diisopropylethylamine, room temperature, 4 to 20 hours, or v) acid anhydride, pyridine, room temperature, 4 to 20 hours, or vi) acid, N hexafluorophosphate, N,N'N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium, N,N-dimethylformamide, N,N-diisopropylethylamine or triethylamine, room temperature, 4 to 20 hours, or vii) acid , N-(3-dimethylaminopropyl)-N"-

88/323 ethylcarbodiimide, — N,N-diisopropylethylamine, N,N-dimethylformamide, — 1-hydroxybenzotriazole hydrate, room temperature, 4 to 20 hours; step c) d) and h) alkyl halide, sodium hydride, tetrahydrofuran or N,N-dimethylformamide, room temperature, 4 to 20 hours; step e) aldehyde or ketone, 1,2-dichloroethane, acetic acid, triacetoxy sodium borohydride, room temperature, 4 to 20 hours; step f) aldehyde or ketone, methanol, acetic acid, triacetoxy sodium borohydride, room temperature, 4 to 20 hours; step k) dihalogen derivative, N,N-dimethylformamide, cesium carbonate, 20-60°C, 10-30 hours.

[00298] Insofar as, in the compound of general formula (1), Rº is hydrogen, R? is -OSi(CH; 3 )>-t-butyl group, the benzazepinathione derivatives of general formula (III) can be prepared by the procedure of Scheme 8: NO? AT THE? AT THE? AT THE? CON a) coa 6) COoAk o) cooH rs Gems Egos Doo: o) PN COM) PO [ D E 2 2 dz R oç o “= (np) ”“- PV) A ic Is Scheme 8

[00299] The keto group of the keto ester of general formula (XVI) - wherein R' is as defined above for general formula (D) and Alk is C1,4alkyl group - is reduced (step a)) and then the group hydroxy of the compound of general formula (XXI) - wherein R' is as defined above for general formula (1) and Alk is C,1alkyl group - is protected by a silyl protecting group (step b)) to obtain the compound of general formula (XXII) - where R' is as defined above

89/323 for formula (1) and Alk is C1,alkyl group. The ester group of the latter is hydrolyzed (step c)), then the nitro group of the compound of general formula thus obtained (XXIII) - wherein R' is as defined above for general formula (D) - is reduced (step d) ) to give the amine derivative of general formula (XXIV) - wherein R' is as defined above for general formula (1) - which is ring-closed by a reagent capable of forming an amide bond (step e)) to obtain the benzazepine of general formula (XXV) - wherein R' is as defined above for general formula (1) - which is reacted with Lawesson's reagent (step £)) to give the benzazepine-thione derivative of general formula (III-b) - where R'! is as defined above for the general formula (1).

[00300] Preferred embodiments are, for example, as follows: step a) sodium borohydride, methanol, room temperature, 4 to 20 hours; step b) 1H-imidazole, tert-butyl-dimethylchlorosilane, N,N-dimethylformamide, room temperature, 4 to 20 hours; step c) lithium hydroxide, methanol, water, tetrahydrofuran, room temperature, 4 to 20 hours; step d) hydrogenation in the presence of a Pt/C catalyst, toluene, room temperature, 4 to 20 hours; step e) N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, N,N-diisopropylethylamine, N,N-dimethylformamide, 1-hydroxybenzotriazole hydrate, room temperature, 4 to 20 hours; step f) Lawesson's reagent, pyridine, 120°C, 4 to 20 hours.

[00301] Compounds of general formula (I-1) can be prepared by reacting compounds of general formula (III-b) and compounds of general formula (ID (Scheme 9):

90 /323 Ora A au DZ 0. Der Ex of > A ' a ' oo mm PÁ mw MA Scheme 9 - where ring B, Y, R' are as defined above for general formula (1), ring A is a cycloalkyl or a saturated 4- to 7-membered heterocycle containing 1 N, in which ring A is attached via the nitrogen in the ring to Y.

[00302] A preferred embodiment is, for example, the following: step a) xylene at 140°C for 20 to 120 hours.

[00303] The silyl protecting group of compounds of general formula (Ii) is removed (Scheme 10) to obtain the hydroxy derivatives of general formula (1I-j), &- TCA) to Mrs É a SO (Fi) *“ . (F)” Scheme 10 - wherein ring B, Y, R' are as defined above for general formula (1), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is fixed via the nitrogen in the Y ring.

[00304] A preferred embodiment is, for example, as follows: step a) tetrabutylammonium fluoride, tetrahydrofuran, room temperature, 3 to 10 hours. hours.

[00305] Insofar as, in the compound of formula (D, Rº and R' together represent -O-(CH2).nO- group and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1N , in which ring A is fixed via the nitrogen in the ring to Y, the compounds of general formula (1) of the present invention are prepared by reaction of compounds of formula (II) SO" (1) - in which ring B and Y are as defined above for the general formula (1) and ring A is a cycloalkyl or a saturated 4 to 7 membered heterocycle containing 1 N, wherein ring A is fixed via the nitrogen in the ring to Y - with the compound prepared in situ from general formula (XXVI), Na CO, O—(CHa)m (XXVI) - wherein R' and m are as defined above for general formula (1).

[00306] The procedure is illustrated in detail in Scheme 11: ” Now, | " Soon LDO, (01) QXVI) (not mm Scheme 11

[00307] A preferred embodiment is, for example, as follows: step a) dichloromethane, trifluoroacetic acid, trimethyloxonium tetrafluoroborate, 40°C, 20 to 40 hours.

[00308] The methoxybenzazepine derivative of general formula (XXVI) can be prepared according to the procedure of Scheme 12:

noz no, ne Ho v q — Sun Rg Fo om 0OVI À poi coma EO Ex EC, R Ex 1) | ' ' x o, O, nel Za a a | CO (H) () (Hk) PXVI Scheme 12

[00309] The keto group of the keto ester of general formula (XVI) is protected by an appropriate a,0-C,.sdiol (step a)) followed by reduction of the nitro group of the compound of general formula (XXVII) - wherein R' in are as defined above for the general formula (1) and Alk is C 1,alkyl group - to give the compound of general formula (XXVIII) (step b)) - where R' in are as defined above for the formula (1) and Alk is C1,4 alkyl group — the latter is ring-closed in the presence of an appropriate base (step c)) to obtain the benzazepine of general formula (XXIX) — where R' and m are as defined above for the general formula (1) and Alk is C1,alkyl group — from the methoxybenzazepine derivative of general formula (XXVI) - wherein R' m are as defined above for general formula (1) and Alk is Craalkyl group - is prepared by methylation (step d)), and the latter without isolation is reacted with an acid hydrazide of general formula (II) (step e)) - wherein ring B and Y are as defined above for the general formula l(1), ring A is a cycloalkyl or saturated 4- to 7-membered heterocycle containing 1 N, in which ring A is fixed via the nitrogen in the ring to Y - to obtain the compound of general formula (Ik) - in which ring B, Y, R' in are as defined above for the general formula (1) and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is fixed via the nitrogen on ring a Y - after removing the ketal protecting group (step f)) to give the oxo compound of general formula (II) — wherein ring B, Y, R' and m are as defined above for general formula (1) and ring A is a cycloalkyl or saturated 4- to 7-membered heterocycle containing 1 N, in which ring A is fixed via the nitrogen in ring a Y - then the latter is reduced (step g)) to obtain the hydroxy derivatives of general formula (Ij ) - wherein ring B, Y, R' and m are as defined above for general formula (1) and ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, wherein ring A is fixed via via the nitrogen in the ring a Y.

[00310] Preferred embodiments are, for example, as follows: step a) trimethyl orthoformate, methanol, ethylene glycol, p-toluenesulfonic acid, 50°C, 50 to 100 hours; step b) hydrogenation in the presence of a Pt/C catalyst, toluene, room temperature, 4 to 20 hours; step c) tetrahydrofuran, potassium tert-butoxide, room temperature, 2 to 20 hours; step d) dichloromethane, trifluoroacetic acid, trimethyloxonium tetrafluoroborate, room temperature, 20 to 25 hours; step e) acid hydrazide of formula (II), dichloromethane, 50°C, 6 to 20 hours; step b) methanol, cc. hydrochloric acid, 70°C, 2 to 6 hours; step g) methanol, sodium borohydride, 0 at 25°C, 2 to 4 hours.

[00311] Compounds of formula (I-k) if desired may also be converted into another compound of general formula (1) by known methods with the introduction of new substituents and/or with the modification, removal of existing substituents.

[00312] The hydroxy derivatives of general formula (Ij) prepared from the compound of general formula (I-1) or the compound of general formula (I-1) if desired can also be converted to another compound of general formula ( D by known methods with the introduction of new substituents and/or with

94 /323 the modification, removal of existing substituents and/or with salt formation and/or with release of the base from the salts and/or with the preparation of enantiomers from racemic mixtures. This is illustrated in detail in Scheme 13: - s " on " 'oRº (HH) (Im) Scheme 13

[00313] Preferred embodiments of step a) of Scheme 13 are, for example, as follows: i) alkyl halide, sodium hydride, tetrahydrofuran or N,N-dimethylformamide, room temperature, 4 to 20 hours, or ii) chloride of acyl, dichloromethane, triethylamine or N,N-diisopropylethylamine, room temperature, 4 to 20 hours, or iii) acyl chloride, pyridine, room temperature, 4 to 20 hours.

[00314] Pure enantiomers can be obtained by chiral HPLC from compounds of general formula (I-]) from acyl and/or alkyl derivatives can also be prepared.

[00315] Insofar as, in the compound of general formula (I), Rº is hydrogen, R? is -NHBoc or R? and R? together represent -O-(CH > )- O- group and ring A is a 4- to 7-membered saturated heterocycle containing 1 or 2 N, in which ring A is attached via a ring nitrogen to the triazole ring of the 5,6 nucleus -dihydro-4H-[1,2,4]triazolo[4,3-a][1|benzazepine, compounds of general formula (I) of the present invention are prepared by reacting compounds of general formula (XXX)

EO(XX) - where ring B and Y are as defined above for the general formula (1) and ring

A is a 4 to 7 membered saturated heterocycle containing 1 or 2 N-e compounds of general formula (XXXI) BON, 2 (XXXI)' - wherein R' is as defined above for general formula (1), R? is hydrogen, R? is -NHBoc or R? and R? together represent -O-(CH> ).n-O- group and m is as defined above for the general formula (1).

[00316] The procedure is illustrated in detail in Scheme 14: . = Mrs i RX Do, Ex + CO, = O, 00X) ROX) am Scheme 14

[00317] Preferred embodiment of step a) of Scheme 14 is for example as follows: i) melting (solvent free) at 120-150°C for 3 to 72 hours.

[00318] Amine derivatives of general formula (XXX) are either commercially available or can be prepared according to the methods described in the Examples.

[00319] As far as how R? is hydrogen, R? is -NHBoc, the triazolo-benzazepine derivatives of general formula (XXXI) can be prepared according to the procedure of Scheme 15 D" NHBoc gw NHBoc & NHBoc (IV-a) XXI) (XXXI-a) Scheme 15

[00320] Compounds of general formula (IV-a) are reacted with formylhydrazine (step a)) and the resulting compound of general formula (XXXII) -

96 / 323 wherein R' is as defined for general formula (1) - is brominated (step b)), thus the bromine derivative of general formula (XXXI-a) is obtained - wherein R'! is as defined above for the general formula (1).

[00321] Preferred embodiments are, for example, as follows: step a) formylhydrazine, 1,4-dioxane, 90°C, 3 to 10 hours; step b) N-bromosuccinimide, tetrahydrofuran, 70°C, 10 to 60 minutes.

[00322] As shown in Scheme 16, compounds of general formula (XXXI-a) are reacted with compound of general formula (XXX) (step a)) - wherein ring B and Y are as defined above for general formula (1) and ring A is a 4- to 7-membered saturated heterocycle containing | or 2 N, in which ring A is attached via a nitrogen in the ring to the triazole ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1 ]|benzazepine nucleus - by removing the protecting group from the resulting compounds of general formula (Io) (step b)), then the amine derivatives thus obtained of general formula (Ip) - wherein ring B, Y and R' are as defined above for the general formula (1) and ring A is a 4- to 7-membered saturated heterocycle containing 1 or 2 N, in which ring A is attached via a ring nitrogen to the triazole ring of the 5,6-dihydro-4H- nucleus. [1,24]triazolo[4,3-a][1|benzazepine - may be sulfonylated, acylated or alkylated (step c)) to obtain compounds of formula (Iq) - in which ring B, Y and R ' are as defined above for general formula (1) and ring A is a 4- to 7-membered saturated heterocycle containing | or 2 N, in which ring A is fixed via a nitrogen in the ring to the triazole ring of the nucleus 5,6-dihydro-4H-[1,24]triazolo[4,3-a][1lbenzazepine and R' is optionally substituted cycloalkyl, C(O)R? or S(O2)R'!º as defined under the meaning of Rº or R* in general formula (1).

97 /323 00) poa 1 (o and GC. OE B (B

Y Y AQ = O (eg Nos (py Scheme 16

[00323] Preferred embodiments are, for example, as follows: step a) melting (solvent free), 120-150°C, 3 to 72 hours; step b) hydrogen chloride in ethyl acetate, room temperature, 4 to 20 hours; step c)i) sulfonyl chloride, pyridine, room temperature, 4 to 20 hours, or 11) sulfonyl chloride, dichloromethane, triethylamine or N,N-diisopropylethylamine, room temperature, 4 to 20 hours, or 111) chloride of acyl, pyridine, room temperature, 4 to 20 hours, or iv) acyl chloride, dichloromethane, triethylamine or N,N-diisopropylethylamine, room temperature, 4 to 20 hours, or v) acid anhydride, pyridine, temperature room, 4 to 20 hours, or vi) acid, N,N,N'N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, N,N-dimethylformamide, N,N-di- isopropylethylamine, room temperature, 4 to 20 hours, or vii) acid, N-(3-dimethylaminopropyl)-N"-ethylcarbodiimide hydrochloride, N,N-diisopropylethylamine, N,N-dimethylformamide, hydrate

98/323 of 1-hydroxybenzotriazole, room temperature, 4 to 20 hours, or viii) alkyl halide, sodium hydride, tetrahydrofuran or N,N-dimethylformamide, room temperature, 4 to 20 hours, or ix) aldehyde or ketone, 1,2-dichloroethane, acetic acid, triacetoxy sodium borohydride, room temperature, 4 to 20 hours.

[00324] When R? and R? together represent -O-(CH>o)-O- group, the triazolo-benzazepine derivatives of general formula (XXXI) can be prepared according to the procedure of Scheme 17: DX) EV EOXI DOXI-b) Scheme 17

[00325] The methoxybenzazepine derivative of general formula (XXVI) obtained in situ from compound of general formula (XXIX) is reacted with formylhydrazine (steps a) and b)) and the resulting compounds of general formula (XXXIII) - where R ' and em are as defined above for the general formula (1) - are brominated (step c)), thus the bromine compounds of the general formula (XXXI-b) are obtained - where R' and em are as defined above for the formula general (1).

[00326] Preferred embodiments are, for example, as follows: step a) dichloromethane, trifluoroacetic acid, trimethyloxonium tetrafluoroborate, room temperature, 20 to 25 hours; step b) formyl hydrazine, dichloromethane, 40°C, optionally solvent change to dioxane, 90°C, 15 to 40 hours; step c) N-bromosuccinimide, tetrahydrofuran, 70°C, 10 to 60 minutes.

[00327] According to Scheme 18, compounds of general formula (XXXI-b) are reacted with compounds of general formula (XXX) (step a)) - wherein ring B and Y are as defined above for the general formula (1) and ring

99 /323 A is a 4- to 7-membered saturated heterocycle containing | or 2 N -, the protecting group from the resulting compounds of general formula (Ir) is removed (step b)), and the resulting keto derivatives of general formula (Is) are reduced (step c)) - where ring B, Y, m and R' are as defined above for general formula (1) and ring A is a 4- to 7-membered saturated heterocycle containing 1 or 2 N, in which ring A is attached via a ring nitrogen to the ring triazole core 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine - to obtain the hydroxy derivatives of general formula (It) which can be acylated or alkylated (step d)), thus compounds of general formula (Iu) are obtained - wherein ring B, Y, R' and Rº are as defined above for general formula (1) and ring A is a 4-4 saturated heterocycle to 7 members containing | or 2 N, in which ring A is attached via a nitrogen in the ring to the triazole ring of the 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine nucleus. A B) and AOS.

KR TC Oro “CO > SÍ, XX) (XXXI-b) sto (1) ng | ob es es O, e es e

LAT OQ CA ay SS ay es) Scheme 18

[00328] Preferred embodiments are, for example, as follows: step a) melting (without solvent), 130 to 140°C, 3 to 72 hours; step b) methanol, cc. hydrochloric acid, 70°C, 2 to 6 hours; step c) methanol, sodium borohydride, 0 at 25°C, 2 to 4 hours; step d) 1) acyl chloride, pyridine, room temperature, 4 hours, or

100 / 323 11) acyl chloride, dichloromethane, triethylamine or N,N-diisopropylethylamine, room temperature, 4 to 20 hours, or ii) alkyl halide, sodium hydride, tetrahydrofuran or N,N-dimethylformamide, room temperature , 4 to 20 hours.

[00329] The hydroxy derivatives of general formula (It) if desired may also be converted into another compound of general formula (1) by known methods with the introduction of new substituents and/or with the modification, removal of existing substituents and/or with salt formation and/or with release of the base from the salts and/or with the preparation of enantiomers from racemic mixtures.

[00330] Insofar as, in the compound of general formula (1), Rº is hydrogen, R? is NRR6 and R* and R taken together with the N to which they are attached form a heterocycle, compounds of general formula (1) of the present invention are prepared according to the procedure of Scheme 19 in a manner that: BA (EX , o Herb (1-5) or (It) (Iv) (-w) Scheme 19

[00331] Compounds of general formula (Ij) or (It) are sulfonylated (step a)) and the resulting compounds of general formula (Iv) are reacted - wherein ring B, Y, ring A and R' are as defined above for the general formula (1) and R” is a methyl, trifluoromethyl or 4-methylphenyl group - with an amine of formula NHR'R' (step b)) - where Rº and Ró taken together with the N to which they are attached form a heterocycle - to obtain compounds of general formula (Iw). Amines of formula NHR'R” are commercially available or can be synthesized by known methods.

[00332] Preferred arrangements are, for example, the following:

step a) 1) sulfonyl chloride, pyridine, room temperature, 4 to 20 hours, or 11) sulfonyl chloride, dichloromethane, triethylamine or N,N-diisopropylethylamine, room temperature, 4 to 20 hours;

[00333] step b) NHRR5, N,N-dimethylformamide, 60 to 120°C, 4 to 24 hours.

[00334] Inasmuch as, in the compounds of general formula (1), R₂ is Cryoalkyl, R₄ is ORS group, compounds of general formula (1) of the present invention are prepared according to Schemes 20 and 21 in a so that: XIX) POXIV) POXV) XXVI à jo ne o A pn A o A uy DXXI) à EOXVII | poxvI The Scheme 20

[00335] The compound of general formula (XXXIV) is protected (step a)) to obtain compounds of general formula (XXXIV) - wherein wherein R' and m are as defined above for general formula (1) and PG! is a protecting group (Peter GM Wuts: Greene's Protective Groups in Organic Synthesis: Sa. ed., Chapter 7. Protection for the Amino Group, pages 895-1193), preferably 4-methoxybenzyl protecting group - and then the ketal is removed with an appropriate acid (step b)), and the obtained oxo derivative of general formula (XXXV) which is reacted with an appropriate lithium alkyl or Grignard reagent (step c)) to obtain the compound of general formula (XXXVD) - wherein R' is as defined above for the general formula (1) and PG' is a protecting group, preferably 4-methoxybenzyl protecting group and R° is C14 alkyl group. By protecting the hydroxy group of compounds of general formula (XXXVI) (step d)), protected hydroxy derivatives of general formula

102/323 (XXXVI]D) - wherein R' is as defined above for the general formula (1), PG' is a protecting group, preferably 4-methoxybenzyl protecting group, R? is Cr,alkyl and PG group? is a protecting group (Peter GM Wuts: Greene's Protective Groups in Organic Synthesis: 5th ed., Chapter 2 Protection for the Hydroxyl Group, including 1,2- and 1,3-diols, pages 17-471), preferably group of silyl protection - are obtained. After deprotection (step e)) of the compounds of the general formula (XXXVIL), then from the compounds thus obtained of the general formula (XXXVIII), the benzazepine-thione derivatives of the general formula (XXXIX) are prepared with Lawesson's reagent (step f)), followed by methylation (step g)) to obtain compounds of general formula (XL).

[00336] Preferred embodiments are, for example, as follows: step a) 4-methoxybenzyl chloride, sodium hydride, N,N-dimethylformamide, 0 at 25°C, 3 to 6 hours; step b) acetic acid, reflux, 6 to 20 hours; step c) 1) alkyl lithium, tetrahydrofuran, (-78)°C, 1 to 4 hours, or ii) RMgClxLiCl, tetrahydrofuran, (-20°C) to (-15°C), 1 to 6 hours, or iii) RMgClxLiCl, tetrahydrofuran, CeCl3, (-78) at 0°C, 12 to 70 hours; step d)1H-imidazole, silyl chloride, N,N-dimethylformamide, room temperature, 4 to 20 hours; step e)i) ammonium cerium nitrate, water, acetonitrile, 0 at 25°C, 6 to 18 hours, or ii) trifluoroacetic acid, dichloromethane, room temperature, 12 to 24 hours, or 11) trifluoromethanesulfonic acid, dichloromethane, room temperature, 2 to 12 hours; step f) Lawesson's reagent, pyridine, reflux, 4 to 5 hours; step g) iodomethane, potassium carbonate, acetone, temperature

103 /323 ambient, 4 to 24 hours.

[00337] Compounds of general formula (XXXIX) or (XL) are reacted with compounds of general formula (II) (step a) of Scheme 21), to give compounds of general formula (Ix) - wherein ring B , Y, ring A and R' are as defined above for the general formula (D), PG? is a protecting group (Peter GM Wuts: Greene's Protective Groups in Organic Synthesis: 5th ed., Chapter 2 Protection for the Hydroxyl Group, including 1,2- and 1,3-diols, pages 17-471), preferably of silica protection, and R? is Cr ,4alkyl group. The protecting group is removed (step b)) from the resulting compounds of general formula (I-x) to obtain compounds of general formula (I-y). For. " and nel" o) ETC, COS OPG? R oPG? R 2 0) coxmxy Is xy 19 e” b) Mrs Era is DE to Do, (5 om * Scheme 21

[00338] The hydroxy derivatives of general formula (Iy) if desired may also be converted into another compound of general formula (1) by known methods with the introduction of new substituents and/or with the modification, removal of existing substituents and/or with salt formation and/or with release of the base from the salts and/or with the preparation of the enantiomers from racemic mixtures, for example using the methods described in step c).

[00339] Preferred modalities are, for example, the following: step a) 1) reaction of (II) and (XXXIX) in xylene at 140°C

104 / 323 for 20 to 150 hours, or 11) reaction of (II) and (XXXIX) in n-butanol at 110°C for 20 to 50 hours, or 111) reaction of (II) and (XXXIX) in 1,4- dioxane at 110ºC for 4 to 20 hours, or 1v) reaction of (II) and (XL) in xylene in the presence of catalytic hydrogen chloride at 140ºC for 4 to 20 hours, or v) reaction of (II) and (XL) in 1,4-dioxane in the presence of catalytic hydrogen chloride at 110°C for 4 to 20 hours; step b) tetrabutylammonium fluoride, tetrahydrofuran, room temperature, 3 to 10 hours; step c) 1) alkyl halide, sodium hydride, tetrahydrofuran or N,N-dimethylformamide, room temperature, 4 to 20 hours, or ii) acyl chloride, dichloromethane, triethylamine or N,N-diisopropylethylamine, room temperature , 4 to 20 hours, or iii) acyl chloride, pyridine, room temperature, 4 to 20 hours.

[00340] Insofar as, in the compound of general formula (1), Rº is hydrogen, R6 is -OCH; group, the benzazepine-thione derivatives of general formula (UI) can be prepared by the procedure of Scheme 22: SE o SE b) SE or Ove — Ove ' OX) ' XL) " 7 o Rº OMe Rº ove OMe db (o) XLN) (XL) Scheme 22

[00341] The hydroxy group of the compound of general formula (XXI) - wherein

R' is as defined above for general formula (1) and Alk is C1,alkyl group - is methylated (step a)) to obtain compound of general formula (XLI) - wherein R' is as defined above for the general formula (1) and AIk is Cr.,alkyl group. The ester group of the latter is hydrolyzed (step b)), then the nitro group of the compound of general formula thus obtained (XLII) - wherein R' is as defined above for general formula (1) - is reduced (step c) ) to give the amine derivative of general formula (XLIII) - wherein R' is as defined above for general formula (1) - which is ring-closed by a reagent capable of forming an amide bond (step d) ) to obtain the benzazepine of general formula (XLIV) - wherein R' is as defined above for general formula (1) — which is reacted with Lawesson's reagent (step e)) to obtain the benzazepine-thione derivative of formula general (III-c) - wherein R' is as defined above for general formula (1).

[00342] Preferred embodiments are, for example, as follows: step a) dichloromethane, 1,8-bis(dimethylamino)naphthalene, trimethyloxonium tetrafluoroborate, room temperature, 20 to 25 hours; step b) sodium hydroxide, methanol, water, room temperature, 4 to 20 hours; step c) hydrogenation in the presence of a Pt/C catalyst, toluene, room temperature, 4 to 20 hours; step d) N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, N,N-diisopropylethylamine, N,N-dimethylformamide, 1-hydroxybenzotriazole hydrate, room temperature, 4 to 20 hours; step e) Lawesson's reagent, tetrahydrofuran, room temperature, 2 to 20 hours;

[00343] Compounds of general formula (I-aa) can be prepared by reacting compounds of general formula (III-c) and compounds of general formula (II) (Scheme 23):

106 / 323 Era. Nua "Ss TPÊ EO Cf =. R OoMe Rg 'OMe o (Io) (aa) Scheme 23 - where ring B, Y, R' are as defined above for the general formula (1), ring A is a cycloalkyl or saturated 4- to 7-membered heterocycle containing 1 N, in which ring A is attached via the nitrogen in the ring to Y.

[00344] A preferred embodiment is, for example, the following: step a) butanol at 140°C for 20 to 120 hours.

[00345] The compound of general formula (I-aa) can also be synthesized from the compound of general formula (XLIV) according to the method shown in Scheme 24. Ora NZ 2 Pa >) DE' (XLIV) (XLV ) (I-aa) Scheme 24

[00346] The compound of general formula (XLIV) is methylated with trimethyloxonium tetrafluoroborate (step a)) and the thus obtained compound of general formula (XLV) is reacted in situ with compound of general formula (II) - in which ring B , Y, R' are as defined above for the general formula (1), ring A is a cycloalkyl or a 4- to 7-membered saturated heterocycle containing 1 N, in which ring A is fixed via the nitrogen in the ring to Y — ( step b)) to obtain compounds of general formula (I-aa).

[00347] A preferred embodiment is, for example, as follows: step a) dichloromethane, trifluoroacetic acid, trimethyloxonium tetrafluoroborate, room temperature, 20 to 40 hours;

step b)i) compound of formula (II), dichloromethane, 40°C, 2 hours ii) compound of formula (ID), acetonitrile, reflux temperature, 1 to 10 hours.

[00348] The "reagent capable of forming an amide bond" used for the preparation of compounds of general formulas (XIII), (XXV) and (XLIV) may be, for example, hydroxybenzotriazole (HOBt) and N-(3) hydrochloride - dimethylaminopropyl)-N"-ethylcarbodiimide (EDC) or O-(benzotriazole-1-11)-N,N,N'N'-tetramethyluronium hexafluorophosphate = (HBTU). The reaction is preferably carried out in the presence of a base - such as triethylamine or N N-diisopropylethylamine (DIPEA) - in an appropriate solvent - such as N,N-dimethylformamide, acetonitrile, hydrocarbons or chlorinated hydrocarbons or mixtures thereof - at between room temperature and 0° C. The reaction is followed by thin layer chromatography Required reaction time is 4 to 20 hours.

[00349] Reagents and detailed process steps required for the above reactions are specified in the Examples.

[00350] An aspect of the present invention are the novel intermediates represented by the general formulas (IMI-a), (II-b), (Ul-c), (IV-a), (XIII), (XXV), (XXIX ) and (XLIV) synthesized in the process to prepare the compound of general formula (1) wherein R' is as defined above for general formula (D), especially (7-chloro-2-0x0-2,3,4, tert-Butyl 5-tetrahydro-1H-1-benzazepin-4-yl)carbamate (Intermediate 3), (7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H-1 tert-butyl-benzazepin-4-yl)carbamate (Intermediate 4), tert-[7-chloro-2-(methylsulfanyl)-4,5-dihydro-3H-1-benzazepin-4-yl]carbamate butyl (Intermediate 5), fert-butyl -(7-bromo-2-OxO-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate (Intermediate 32), (7 -bromo-2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate — from — tert-butyl (Intermediate 33), T7-bromo-1,5- dihydrospiro[1-benzazepine-4.2"-

108 / 323 [1,3]dioxolane]-2(3H)-one (Intermediate 36), 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolane] -2(3H)-one (Intermediate 53), 4-([tert-butyl(dimethyl)silylJox1)-7-chloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Intermediate — 62), 4-([tert-butyl(dimethyl)silylJoxy)-7-chloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-thione (Intermediate 63), 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (step d) of Intermediate 103) or 7-chloro-4-methoxy-1,3, 4,5-tetrahydro-2H-1-benzazepine-2-thione — (Intermediate 103).

[00351] The activity data of each of the compounds of general formula (1) of the present invention are determined in vitro and in vivo by the methods described below.

Vla receptor binding assay for human vasopressin Cells and radioligand

[00352] The immortalized 1321N1 cell line (Perkin Elmer, ES-361-M400-UA) constitutively and stably expressing Vla receptor for human vasopressin and vasopressin (8-L-Arginine), labeled compound [Phenillanyl-3,4, 5-"H(N)] (Perkin Elmer Life and Analytical Sciences) as radioligand were used to determine the affinity of the prepared compounds.

Method

[00353] Membrane preparation: The preparation of membranes from immortalized 132IN1I cells expressing propagated human Vla receptor for Vasopressin was done according to the method of Jarvis ( Jarvis et al., J Pharmacol Exp Ther 2004, 310:407-16 ). Cells were suspended in preparative buffer (50 mM Tris, 1 mM EDTA, 0.1 MM PMSF) and homogenized with glass homogenization technique. To separate the crude membrane fraction, two consecutive centrifugation procedures (40,000 g for 20 minutes at 4°C) were performed, then the

109 / 323 The membrane was taken up in the preparative buffer during a final washing step, it was divided into aliquots which were stored at -80°C until the time of measurement.

[00354] The protein content of the prepared membrane was determined according to Lowry's method using bovine serum albumin (BSA) standard dilution strain (Lowry et al, J Biol Chem 1951, 193:265-75).

[00355] Receptor Binding Test: In the receptor binding assay, substances with unknown affinity were used at a minimum of 8 different concentrations, with 3 parallels at each concentration. To determine the final affinity value, the results of at least two independent experiments were taken into account. The assay mix included incubation buffer (50 mM Tris-HCl, pH 7.4 + 3% BSA), membrane preparation of 1321N1 cells expressing the Vla receptor for human Vasopressin (167 µg/ml) and Vasopressin (8 -L-Arginine), [phenylalanyl-3,4,5-º*H(N)] as radioligand (1 nM).

[00356] Non-specific binding values were determined in the presence of unlabeled 1.2x10º M (Argº)-vasopressin. Samples were incubated in a total volume of 0.33 ml for 60 minutes at 27°C. Membrane-bound and free ligands were separated by filtration through a 0.5% UniFilterO GF/B'Y impregnated with polyethyleneimine. After drying the filter plates, 40 µl of Microscint-20 scintillation cocktail (Packard) was added to the samples. Finally, radioactivity was measured using MicroBeta? (Perkin Elmer).

[00357] The ICsº data (ie, the concentration of the unknown substance that displaces 50% of specific bound radioligand) is calculated from the concentration shift curve using the mathematical sigmoidal fit method y = (AI-A2)/ (1+(X/Xo)D)+A2 with Origin 7.5 software. (OriginLab Corporation, Northampton, USA). During tuning, asymptotes are not fixed. The K values; (inhibition constant) are given with the Cheng-Prusoff equation K;=ICso/[1+(L/Kp)] where [L] is the concentration of the radioligand used in the experiment and [Kp] is the affinity of the radioactive ligand labeled for the given receiver. Kp is previously determined using the Scatchard curve.

Functional assay to test compounds in cell line expressing Vla receptor for human vasopressin Cells

[00358] The immortalized 1321N1 cell line (Perkin Elmer, ES-361-M400-UA) constitutively and stably expressing Vla receptor for human vasopressin was used to measure the prepared compounds. The measured GPCR receptor ordinary secondary messenger pathway was used, the endogenous G-associated system.

methods

[00359] Using 30,000 cells/plate, compounds were measured in 96-well plates. The buffer composition of the measurements was as follows (expressed in mM): 140 NaCl, 5 KCl, 2 CaCl, 2 MgCb, 10 glucose, 10 HEPES (4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid), 2 probenecid, pH = 7.4. FLIPR Calcium 5 Kit (Molecular Devices) was used as the fluorescent dye, the medium was not removed before filling with the dye, and the cells were not washed either before or after. Incubation was carried out at room temperature, the final concentration of DMSO was 1%. Materials to be measured were administered 15 to 20 minutes before treatment, at least two parallels of each compound at each concentration were measured.

[00360] Fluorescence signal was used to determine intracellular Ca” level, reader was FlexStation 1196. Cytoplasmic Ca” concentrations were measured by fluorometry using FlexStation 1196 plate reader (excitation: 485 nm, emission: 525 nm) . The fluorescence signal was connected every 1.4 seconds for 1 minute. The reference compounds used were the following: (Argº)-vasopressin as agonist at ECgo concentration, determined for each plate, and relcovaptan as antagonist at 1 µM. the % inhibition at each concentration and the ICs value of the compounds were determined where a concentration line was also measured.

[00361] The total AVP concentration-response curve was recorded on each plate. The effect of the measured compounds was expressed as percentage of relative inhibition compared to the control response. For the graphical representation of the data, alignments of four non-linear parameters were applied using SoftMaxPro software according to the following formula: y = AD/(1+(«/C)"B)+D, where: A = 0 and D = 100 - lower/upper fixed asymptotes, y = percentage inhibition, x = logarithm of concentrations of the tested compound, B = slope of the curve, and C — ICso (the concentration belonging to 50% inhibition of the control response). Mean ICso values were calculated from at least three independent measurements in all cases Table 1: Efficacy of compounds of the present invention measured in V1la receptor binding assay for vasopressin and functional assay Example Ki (a0M) 1Cso ( MD) Ki (nM) IC (OM) No in lineage of | in lineage of Example No | in lineage of | in lineage hV cells 1a cells hV1a cells hV1a cells hVla cells La a og [| a ||

NY NA NY RS RS O E Ls | 38 [| the | 3 |] 23 | 23 || 8 Do aa | 68 game | o7 | sa || L8 14 15 u 32 17 260 P 0.8 3 5 21 480 u L1 52 700 04 97 160 16 3 36 610 Pr | 21 7 | 100 Las [os] 1 j 3 | 2 | 30 |

La Doo oa | 8th |

7. K; (nM) 1Cso (9nM) " K;(nM) 1Cso (nM) : hV1a cells hV1a cells : hV1a cells hV1a cells 46 | 3 [| no pp | mo | 22 | LaB as | 309 pg paid ae | 49 |] ss [| ao | 17 Don | 185 | se |] 7 [| 3 [so | 58 | 56 | La | 36 [| 5 | | eo | 14 | 54 0.6 aaa 55 03 56 03 Par ds Doo [Paid ST 03 E 03 59 0.8 25 ds | oa | 19 | 60 20 [as | so | 102 [| 15 | 61 04 62 02 Pa a 3 03 64 0.5 aaa ag 65 os 66 0.8 67 0.6 68 94 Po 33 a Da ag 69 10 OE o Dr La DD oa o ao oa as | K; (nM) 1Cso (nM) K; (nM) 1Cso (nM) ' hVla cells hV1a cells ' hV1a cells hVla cells 101 0.2 102 5.9 103 0.2 104 0.2 | os | 13 | o | 145 | os aaa ass Rj aaa ag 7) g9 | Lu o] 365 [| 535 ag | 3 Bo us Doo a ag aa 7 Lu | oo [| 43 a | o | oa | us Do o ass ao a ns DA a ago og as |

TP 79 12 3 123 21 Les | the [| 18 [as | the | the | Le | the [| 53 pas Dog ns | K;(nM) ICso (nM) in K;(nM) TICso (9M)

: emhVla cells on hVla ' hVla cells hVla cells Lake] aB [pa an oa 9 | 166 6.2 167 04 168 04 og js DD o | the | 169 0.9 23 da Doo Aug 170 15.3 mm 0.6 72 07 173 L6 17 07 505 176 04 Pao 26 | the | oo | 7 03 178 3.9 Po dB Poa 179 0.2 180 L! rim os an o o a3 | LB | the [5535 as | 66 | 6 |

K; (nM) 1ICso (9M) K;(nM) TCso (9M)

Example in lineage of | in lineage of | Example in lineage of in lineage of

No. hVla cells hV1a cells No. hVla cells hVla cells 21 0.9 2 58 223 L6 224 0.7 48 226 0.5 27 LO 228 0.8 229 04 230 07

114 /323 233 6.9 234 3.8

FE Lar Dora E | Mouse Vla receptor binding assay for vasopressin Cells and radioligand

[00362] The immortalized cell line 1321IN1I (clone B9/1321N]1) constitutively and stably expressing Vla receptor for mouse vasopressin, vasopressin (8-L-Arginine), labeled compound [phenylalanyl-3,4,5-" H(N)] (Perkin Elmer Life and Analytical Sciences) as radioligand were used to determine the affinity of the prepared compounds.

Method

[00363] Membrane preparation: Membrane preparation of 1321IN]I immortalized cells expressing the propagated mouse Vla receptor for Vasopressin was done according to the method of Jarvis (Jarvis et al., J Pharmacol Exp Ther 2004, 310: 407-16). Cells were suspended in preparative buffer (50 mM Tris, 1 MM EDTA, 0.1 mM PMSF) and homogenized with glass homogenization technique. To separate the crude membrane fraction, two consecutive centrifugation procedures (40,000 g for 25 minutes at 4°C) were performed, then the membrane was taken up in the preparatory buffer during a final washing step, it was divided into aliquots which were stored at room temperature. -80ºC until the time of measurement.

[00364] The protein content of the prepared membrane was determined according to Lowry's method using bovine serum albumin (BSA) standard dilution strain (Lowry et al, J Biol Chem 1951, 193:265-75).

[00365] Receptor binding test: In the receptor binding assay, substances with unknown affinity were used at a minimum of 8 different concentrations, with 3 parallels at each concentration. To determine the final affinity value, the results of at least two independent experiments were taken into account. The assay mix included incubation buffer (50 mM Tris-HCl, pH 7.4 + 3% BSA), membrane preparation of 1321N1 cells expressing the mouse Vla receptor for vasopressin (152 µg/ml) and vasopressin ( 8-L-Arginine), [Phenylalanyl-3,4,5-*H(N)] as radioligand (concentration of -35-50% Kp).

[00366] Non-specific binding values were determined in the presence of an unlabeled 1.2x10º M (Arg*)-vasopressin. Samples were incubated in a total volume of 0.33 ml for 60 minutes at 27°C. Membrane-bound and free ligands were separated by filtration through a UniFilter&6 GF/B!M impregnated with 0.5% polyethyleneimine. After drying the filter plates, 40 µl of Microscint-20 scintillation cocktail (Packard) was added to the samples. Finally, radioactivity was measured using MicroBeta? (Perkin Elmer).

[00367] The radioligand binding capacity of a substance is determined in at least two independent experiments. Specific radioligand binding can be defined as the difference between total and non-specific binding in the presence of a saturating amount of the unlabeled ligand or different concentrations of the substance being tested. Results are given as a percentage of inhibition of specific binding obtained in the presence of the substance to be tested.

[00368] ICsº data (ie the concentration of the unknown substance that displaces 50% of specific bound radioligand) is calculated from the concentration shift curve using the sigmoidal fit mathematical method y = (AI-A2)/ (1+(X/Xo)D)+A2 with Origin 7.5 software. (OriginLab Corporation, Northampton, USA). During tuning, asymptotes are not fixed. The K values; (inhibition constant)

are given with the Cheng-Prusoff equation K;=ICso/[1+(L/Kp)] where [L] is the concentration of the radioligand used in the experiment and [Kp] is the affinity of the radioactively labeled ligand for the given receptor . Kp is previously determined using the Scatchard curve. Table 2: Binding affinity of some compounds of the present invention measured in mouse vasopressin K Vla receptor binding assay; (oM) Nr DS RS LL 9 | 3 | |

NS RS La as V2 receptor binding assay for human vasopressin Cells and radioligand

[00369] The immortalized cell line 1321IN1 (Perkin Elmer, ES-363-M400U A)(LotNo: 1765208) stably and constitutively expressing receptor for human vasopressin V2, CHO-K1 cell membrane expressing receptor for human Vasopressin V2 (Perkin Elmer , 6110541400UA) and vasopressin (8-L-Arginine), labeled compound [Phenylalanyl-3,4,5-*H(N)] (Perkin Elmer Life and Analytical Sciences) as radioligand were used to determine the affinity of the prepared compounds.

Method

[00370] Receptor binding test: In the receptor binding assay, substances with unknown affinity were used at a minimum of 8 different concentrations, with 3 parallels at each concentration. To determine the final affinity value, the results of at least two

117/323 independent experiments were taken into account. The assay mix included incubation buffer (50 mM Tris-HCl, pH 7.4 + 3% BSA), membrane preparation of 1321IN1 cells expressing the receptor for human vasopressin V2 (1.82 µg/ml) and Vasopressin ( 8-L-Arginine), [Phenylalanyl-3,4,5-*H(N)] as radioligand (- Kp concentration).

[00371] Non-specific binding values were determined in the presence of an unlabeled vasopressin 1.2x10º M (Arg*)-. Samples were incubated in a total volume of 0.55 ml for 90 minutes at 27°C. Membrane-bound and free ligands were separated by filtration through a UniFilter& GF/B'!M impregnated with 0.5% polyethyleneimine. After drying the filter plates, 40 µl of Microscint-20 scintillation cocktail (Packard) was added to the samples. Finally, radioactivity was measured using MicroBeta? (Perkin Elmer).

[00372] The radioligand displacement capacity of a substance is determined in at least two independent experiments. Specific radioligand binding can be defined as the difference between total and non-specific binding in the presence of a saturating amount of the unlabeled ligand or different concentrations of the substance being tested. Results are given as a percentage of inhibition of specific binding obtained in the presence of the substance to be tested.

[00373] ICso data (i.e. the concentration of the unknown substance that displaces 50% of specific bound radioligand) is calculated from the concentration shift curve using the mathematical sigmoidal fit method y = (A1-A2)/ (1+(x/Xo)D)+A2 with Origin 7.5 software. (OriginLab Corporation, Northampton, USA). During tuning, asymptotes are not fixed. The K values; (inhibition constant) are given with the Cheng-Prusoff equation K;=ICsy/[1+(L/Kp)] where [L] is the concentration of the radioligand used in the experiment and [Kp] is the affinity of the radioactive ligand labeled for the given receiver. Kp is previously determined using the Scatchard curve. Table 3: Binding affinity of some compounds of the present invention measured in receptor binding assay for human vasopressin V2 in 1321N1 Kiou cell line Example No. % IuM inhibition in hV2 132IN1 Le BB Lo 8 cell line | 360M | Lo 9 - name || La MO | 57 446 nM 62 53 nM Method

[00374] Receptor binding assays were performed at at least 8 concentrations, with two or, better, three samples at each concentration, in at least two independent experiments using an incubation buffer (50 mM Tris-HCl, 5 mM MgCl, pH 7.4 + 0.1% BSA), membrane preparation of CHO-K1 cells (Perkin Elmer, 6110541400UA) expressing the receptor for human vasopressin V2 (7 ug/ul) and Vasopressin (8-L-Arginine), [ Phenylalanyl-3,4,5-ºH(N)] as radioligand (- Kp concentration).

[00375] Non-specific binding values can be determined in the presence of an unlabeled 1.2 x 10º M (Arg”) vasopressin. Samples were incubated in a total volume of 0.55 mL for 90 minutes at 27°C. Membrane-bound and free ligands were separated by filtration through a UniFilter& GF/B"Y impregnated with polyethyleneimine. The filter plates were washed three times with 0.5 ml ice-cold wash buffer (50 mM Tris-HCl, pH 7 After drying the filter plates, 40 µl of Microscint20 scintillation cocktail (Packard) was added to each well.Finally, radioactivity was measured using Tri-Carb 2900TR liquid scintillation analyzer (Perkin Elmer).

[00376] The radioligand displacement capacity of a substance is determined in at least two independent experiments. Specific radioligand binding can be defined as the difference between total and non-specific binding in the presence of a saturating amount of the unlabeled ligand or different concentrations of the substance being tested. Results are given as a percentage of inhibition of specific binding obtained in the presence of the substance to be tested.

[00377] ICso data (i.e., concentration of unknown substance that displaces 50% of specific bound radioligand) is calculated from the concentration shift curve using the mathematical sigmoidal fit method y = (AI-A2)/ (1+(X/Xo)D)+A2 with Origin 7.5 software. (OriginLab Corporation, Northampton, USA). During tuning, asymptotes are not fixed. The K values; (inhibition constant) are given with the Cheng-Prusoff equation K;=ICso/[1+(L/Kp)] where [L] is the concentration of the radioligand used in the experiment and [Kp] is the affinity of the radioactive ligand labeled for the given receiver. Kp is previously determined using the Scatchard curve.

[00378] Affinity (K;) data measured on the 1321N1 cell line expressing human vasopressin V2 receptor are in very close correlation with the K results; generated with CHO-K1 cell line expressing receptor for human vasopressin V2.

In vivo test of functional Vla Animals

[00379] Male mice (NMRI, ToxiCoop) weighing 18-40 g were used. Animals were kept for at least 5 days after delivery,

120 / 323 during housing and measurements they were fed and water ad libitum. The experiments were permitted by the Local Committee for Animal Protection and carried out in accordance with European animal protection guidelines (EU Directive 2010/63/EU). Method

[00380] The behavior of the animals was measured by an analysis system — behavioral “automated (LABORAST'M). Sensors located below platforms detect the mechanical vibration generated by the animal's movement, and transform it into an electrical signal (Quinn et al., J Neurosci Methods 2003, 130:83-92). After analyzing the signals, the system analyzes the time spent with the following behavioral parameters: locomotion, immobility, climbing, hygiene care. The hygiene care algorithm, by definition, is capable of measuring the behavioral response to scratching. During the experiment, the mice were pre-treated with the test substance or vehicle and after the pre-treatment period, the scratch-inducing compound (sc 0.3 mg/kg oxytocin) was administered and then the animals were placed individually in measuring cages. Its behavior was observed for 1 hour. To reduce exploratory activity, the animals were measured after one hour of habituation to the cage. Behavioral parameters were compared with parameters measured in parallels from control animals.

[00381] The behavioral inhibitory effect of the substances was calculated with mean values of vehicle-treated groups measured in parallel and presented as a percentage of inhibition: 0% was expressed as the mean value of scratching behavior of animals pre-treated with vehicle (and pre-treated). -treated with sc physiological saline vehicle), while 100% was expressed as the mean scratch value in vehicle pre-treated animals that received oxytocin subcutaneously. For statistical analysis, one-way analysis of variance (ANOVA) was used with the

121/323 Tukey's post hoc test.

[00382] Surprisingly, it was found that some compounds of the present invention produced significant effect in the in vivo functional test of the mouse Vla receptor. Table 4: The effectiveness of some compounds of the present invention in the in vivo mouse Vla functional test: inhibition of oxytocin-induced scratching behavioral response after pretreatment with mg/kg p.o. in mice.

LL 8 | & | 6 | 4 | Lo | 106 | 6 | 76 | Ls | & | the [| 108 | Ls | the | 1 | an | Ls | the | 204 [| 6 | there | an | 356 | 6 | aa *after i.p. treatment

The prenatal valproate model of autism spectrum disorder (ASD) in rats

[00383] The prenatal valproate model has excellent construction and face validity, thus it is an animal model of ASD (Christensen et al, JAMA 2013, 309:1696-1703; Roullet et al, Neurotoxicol Teratol. 2013, 36 :45-56). In this model, period mated female Wistar rats (Harlan, UK) were treated with a single dose of valproic acid (VPA, i.p. 600 mg/kg) at 12.5 days of pregnancy. After birth and separation, the male pups examined were kept under standard laboratory conditions until the completion of the studies. Four animals were kept together in standard cages at an external temperature of 22-24ºC and on a 12-12 hour light-dark cycle (07.30 a.m. -07.30 p.m.). food and water

122/323 were available ad libitum. After once-daily treatment with the test substance for 7 days and pre-treatment on the measurement day, the behavior of the rats was evaluated in the social preference test on the 59th or 60th postnatal day. Social preference testing is a widely accepted testing method for determining autistic behavior in rodents (Nadler et al, Genes Brain Behav 2004, 3:303-314; Bambini-Junior et al, Brain Res 2011, 1408:8-16 ). The test consists of two paradigms, the first is the social approach avoidance test. In this paradigm, the social behavior of examined animals can be determined with a special three-chamber device. In the apparatus, the contact behavior of the conspecific area and the separate empty area surrounded by a perforated wall can be examined and compared. Prenatally treated rats with valproate produce autistic behavior and spend significantly less time searching for conspecific responses than vehicle-treated control animals in utero. A day later, on the 60th postnatal day, rats were tested in the social memory and recognition paradigm. In this, contact behavior with a previously unknown new conspecific can be measured compared to a familiar conspecific.

[00384] In the social avoidance paradigm, valproate-treated rats (VPA/VEH) showed a significant decrease in active time spent on social behavior compared to vehicle-treated control animals in utero (VEH/VEH). Some 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine compounds of the present invention substituted at the 5-position were unexpectedly effective in this test and treatment in a statistically significant manner. reversed the VPA/VEH value to the value of animals treated with VEH/VEH.

[00385] Rats treated with SAHA (suberoil anilide or vorinostat) used as a positive control also showed a statistically significant increase in time spent with social search response

123/323 (Foley et al, Eur J Pharmacol 2014, 727:80-86).

[00386] In the social memory recognition paradigm, rats treated with valproate showed a significant decrease in active time spent searching for new unfamiliar animals, compared to vehicle-treated control animals in utero. Some 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]/benzazepine compounds of the present invention substituted in position 5 make the behavior of animals more socialized and were able to significantly increase the active time spent searching for responses from new animals. Unexpectedly, the treatment reversed the VPA/VEH value to the value of animals treated with VEH/VEH. SAHA-treated rats used as a positive control also showed a statistically significant increase in time spent searching for answers.

[00387] Certain compounds of the present invention thus exhibited significant behavioral benefits in the present animal model implicating clinical symptoms of ASD, thus offering a therapeutic opportunity for the treatment of human ASD symptoms. Table 1: Effects on active contact time on social avoidance approach and social memory recognition paradigms of some compounds of the present invention contact time contact time Po % active effect with % active effect[sec] novelty|sec] Example 26 VEH/VEH 147.1 4138 PD 3676] “| VPA/VEH an1x82 | | 18.0+ 6.2 Lo

PA AA 156.0 6.7 155.5 5.8 PE pw 26 1.5 mg/kg i.p. TL2+15.9 83.7 11.8 1164 22.5 133.5 + 10.0 mg/kg 148.7 8.3 141.9 +9.1 The data presented in the table are shown as mean + standard error of the mean (SEM) and rounded to a decimal. Percentages were calculated from raw data and rounded to integers (where VEH/VEH = 100%, VPA/VEH = 0%).

[00388] The present invention will be further illustrated by the following

124 / 323 embodiments, without limiting the scope of the present invention thereto. From part of the above description and examples, one skilled in the art can verify the essential features of the invention and, without departing from its essence and scope, can make some changes and modifications to adapt the invention to various applications and conditions. As a result, the invention is not limited to the following illustrative examples, but, in fact, to the scope determined by the appended claims.

[00389] In general, the compounds of general formula (1) can be prepared according to the common general knowledge of those skilled in the art and/or the methods described for the working examples and/or intermediates. Solvents, temperatures, pressures and other reaction conditions can be readily selected by those skilled in the art. Starting materials are commercially available and/or can be readily prepared by those skilled in the art. During the preparation of the compounds, combinatorial techniques may be used, for example, where the present intermediate groups are appropriate for the use of these methods.

[00390] In the description of the syntheses, the following terms and abbreviations were used: dry = anhydrous Boc = tert-butoxycarbonyl DIPEA = N,N-diisopropyl-ethylamine DMAP = 4-dimethylamino-pyridine DMF = N N-dimethylformamide EDC = hydrochloride — de — N-(3-dimethylaminopropyl)-N'-ethyl carbodiimide HOBt = 1-hydroxybenzotriazole hydrate HBTU = N,N,N',N'-tetramethyl-O-(1H-benzotriazole-1 hexafluorophosphate -yl)uronium K2CO; = potassium carbonate

125 /323 Lawesson's reagent = 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphitane-2,4-Meldrum's acid disulfide = 2,2-dimethyl-1,3-dioxane-4 ,6-dione MgSO1 = magnesium sulfate NaBH, = sodium borohydride NaBH(OAc); = triacetoxy sodium borohydride NaHCO; = sodium bicarbonate NaCl = sodium chloride NaxCO; = sodium carbonate NaOH = sodium hydroxide NasSO,s = sodium sulfate Pd/C = palladium on carbon Phg = phenylglycine PVC = platinum on carbon THF = tetrahydrofuran Intermediate 1 acid 3-[(ferc-butoxycarbonyl)amino]-4- (5-Chloro-2-nitrophenyl)butanoic KW NHBoc and Method A) a) 2-[(tert-butoxycarbonyl)Jamino]-3-(5-chloro-2-nitrophenyl)propanoic acid Coon c

[00391] To a cooled and stirred mixture of acid 3.03 g (12.4 mmol) of 2-amino-3-(5-chloro-2-nitrophenyl)propanoic acid (NA Meanwell et al., J Med Chem 1991, 34:2906-2916), 55 ml of 1,4-dioxane, 12 ml of water and 12.4 ml of 10% NaOH solution, 3.35 g of di-tert-butyl dicarbonate (15.4

126 / 323 mmol) was added and the mixture was stirred at room temperature overnight. after completing the reaction, the pH of the mixture was adjusted to 7 with 10% hydrochloric acid solution, and it was concentrated. Dichloromethane was added to the residue and stirred at room temperature for 1 hour. The precipitated solid was filtered, washed with dichloromethane, the filtrate was concentrated and the residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 3.83 g (90%) of the title product was obtained. MS (ESI) m/z 367.1 (M+Na)*. b) N-[1-(5-chloro-2-nitrophenyl)-4-diazo-3-oxobutan-2-yl | tert -butyl carbamate c º San

[00392] A mixture of 2.55 g (74 mmol) of 2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-nitrophenyl)propanoic acid, 40 mL of diethyl ether and 1.25 mL (9.0 mmol) of triethylamine was cooled to -30°C and 1.15 mL (8.9 mmol) of isobutyl chloroformate was added dropwise with stirring. The mixture was stirred at -30°C for 15 minutes, then a solution of 0.7M diazomethane in 50 ml of diethyl ether was added dropwise to maintain the temperature between -25°C and -30°C. The mixture was allowed to warm to 0°C and stirred at this temperature for 1 hour, then excess diazomethane was decomposed with acetic acid. The reaction mixture was diluted with ethyl acetate, the pH adjusted to 7 with NAHCO solution; saturated solution, the phases were separated and the organic phase was washed with saturated NaCl solution, dried over anhydrous Na:SO, filtered and concentrated. The residue "was purified by column chromatography using dichloromethane:methanol=95:5 as eluent. Thus, 1.72 g (63%) of the title product was obtained. MS (ESI) m/z 391.1 (M+Na)*. c) 3-[(tert-butoxycarbonyl)amino]-4-(5-chloro-2-nitrophenyl)butanoic acid

127 /323 Y cooH

[00393] A mixture of 8.26 g (224 mmol) of tert-butyl N-[1-(5-chloro-2-nitrophenyl)-4-diazo-3-oxobutan-2-yl]carbamate, 300 mL of 1,4-dioxane, 60 mL of water and 0.49 g (2.1 mmol) of silver benzoate was stirred at room temperature for 20 hours, then diluted with 300 mL of ethyl acetate, 300 mL of 5% hydrochloric acid was added and the phases were separated. The organic phase was washed with saturated NaCl, dried over anhydrous Na7SO, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 5.28 g (66%) of the title product was obtained. MS (ESID) m/z 381.1 (M+Na)*. Method B) a) 5-[2-(5-chloro-2-nitrophenyl)-1-hydroxyethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione Ox o.

SR on the

[00394] 4.925 g (22.84 mmol) of (5-chloro-2-nitrophenyl)acetic acid (Enamine Ltd.) were dissolved in 250 ml of acetonitrile and 8.95 ml (51.4 mmol) of DIPEA, 279 mg (2.3 mmol) of DMAP and 3.72 g (25.1 mmol) of Meldrum's acid were added with stirring. After cooling, 3.1 mL (25.1 mmol) of pivaloyl chloride was slowly added dropwise to keep the temperature below 30°C. The reaction mixture was stirred for 4 hours at 45°C, then the solution was cooled to 0°C and 90 ml of 1N hydrochloric acid and 90 ml of water were added. The precipitated material was filtered, washed with water, and dried. Thus, 6.62 g (85%) of the title product was obtained as a white powder which was used without further purification in the next step.

b) Methyl 4-5-chloro-2-nitrophenyl)-3-oxobutanoate

OS to

[00395] A mixture of 6.62 g (194 mmol) of 5-[2-(5-chloro-2-nitrophenyl)-1-hydroxyethylidene]-2,2-dimethyl-1,3-dioxane-4,6 -dione, 70 ml of methanol and 280 ml of toluene was refluxed for 3 hours. The mixture was cooled to room temperature, 130 ml of saturated NaCl and 100 ml of ethyl acetate were added, the phases were separated, the organic phase was dried over anhydrous MgSO4, filtered and concentrated. Thus, 5.21 g (99%) of the title product was obtained as a cream-colored oil, which was permanently crystallized within a few days. MS (ESI) m/z 272.1 (M+H)*. c) methyl 3-amino-4-5-chloro-2-nitrophenyl)but-2-enoate Y 2

[00396] A mixture of 5.40 g (20 mmol) of methyl 4-(5-chloro-2-nitrophenyl)-3-oxobutanoate, 60 mL of methanol and 7.8 g (101 mmol) of ammonium acetate was heated at reflux for 5 hours then concentrated. To the NaHCO solution; saturated solution was added to the residue and extracted with dichloromethane. The organic phase was dried over anhydrous MgSO, filtered and concentrated. Thus, 4.85 g (90%) of the title product was obtained as a yellow solid. MS (ESI) m/z 271.7 (M+H)*. d methyl 3-amino-4-(5-chloro-2-nitrophenyl)butanoate SE" to

[00397] 11.23 g (41.5 mmol) of methyl 3-amino-4-(5-chloro-2-nitrophenyl)but-2-enoate was dissolved in 120 mL of acetic acid and 6.27 g ( 29.6 mmol) of NaBH(OAc);3 was added during cooling and stirring. The mixture was stirred at room temperature for 2 hours and a further 6.27 g

129 /323 (29.6 mmol) of NaBH(OAc); were added. The reaction mixture was stirred at room temperature for 20 hours and poured into ice water. The pH of the mixture was adjusted to 8 with K2CO; solid and extracted with ethyl acetate, the organic phase was dried over MgSO, anhydrous, filtered and concentrated. Thus, 11.32 g (100%) of the title product was obtained as a yellow oil. MS (ESI) m/z 273.7 (M+H)*. e) methyl 3-[(tert-butoxycarbonyl)amino]-4-(5-chloro-2-nitrophenyl)butanoate W NHBoc

OT to

[00398] To a mixture of 11.32 g (41.5 mmol) of methyl 3-amino-4-(5-chloro-2-nitrophenyl)butanoate, 330 mL of methanol and 6.82 g (82.4 mmol) of NaHCO; 11.32 g (51.9 mmol) of di-fert-butyl dicarbonate was added during cooling and stirring and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated, 500 mL of water was added to the residue, the precipitated product was filtered, washed with water, and dried. Thus, 13.83 g (89%) of the title product was obtained as a yellow powder. MS (ESI) m/z 395.0 (M+Na)*. D 3-[(tert-butoxycarbonyl)amino]-4-(5-chloro-2-nitrophenyl)butanoic acid K NHBoc and

[00399] To a stirred mixture of 13.83 g (37.1 mmol) of methyl 3-[(tert-butoxycarbonyl)amino]-4-(5-chloro-2-nitrophenyl)butanoate, 260 mL of THF, 130 ml of methanol and 130 ml of water, 8 g (190 mmol) of lithium hydroxide monohydrate were added while stirring. The reaction mixture was stirred at room temperature for 20 hours and then concentrated. 300 ml of water was added to the residue, the pH of the mixture was adjusted to with 10% hydrochloric acid and the mixture was stirred at room temperature for 1 hour. The precipitated product was filtered, washed with water, and dried.

Thus, 13.2 g (99%) of the title product was obtained. MS (ESD) m/z 381.1 (M+Na)*.

Intermediate 2 4-(2-amino-5-chlorophenyl)-3-[(fert-butoxycarbonyl)amino]butanoic acid Y'cooH Method A)

[00400] To a mixture of 5.28 g (14.7 mmol) of 3-[(tert-butoxycarbonyl)amino]-4-(5-chloro-2-nitrophenyl)butanoic acid — (Intermediate 1), 140 mL of methanol and 350 mg (1.47 mmol) of nickel chloride hexahydrate, 1.35 g (35.7 mmol) of NaBH were added under ice-cooling, then the reaction mixture was stirred at room temperature for 20 hours. . The reaction mixture was adjusted to pH 6 with 10% hydrochloric acid, the mixture was filtered through Celite, the filtrate was concentrated and the residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 2.11 g (44%) of the title product was obtained. MS (ESI) m/z 351.2 (M+Na)*.

Method B)

[00401] To a mixture of 3.0 g (8.34 mmol) of 3-[(tert-butoxycarbonyl)amino]-4-(5-chloro-2-nitrophenyl)butanoic acid (Intermediate 1) and 400 mL of toluene, 300 mg of 5% Pt/C catalyst was added under argon, then the reaction mixture was stirred at room temperature in a hydrogen atmosphere. After the reaction was complete, the catalyst was filtered through Celite, washed with methanol, and the filtrate was concentrated. Thus, 2.64 g (96%) of the title product was obtained.

Intermediate 3 (ferc-butyl 7-chloro-2-OxO-2,3,4,5-tetrahydro-1H-1-benzazepin-4-iDcarbamate

131 / 323 NHBoc

[00402] A mixture of 5.52 g (16.79 mmol) of 4-(2-amino-5-chlorophenyl)-3-[(tert-butoxycarbonyl)amino]butanoic acid (Intermediate 2), 60 mL of DMF , 3.9 g (20.34 mmol) of EDC, 7 mL (40.2 mmol) of DIPEA and 3.08 g (20.1 mmol) of HOBt was stirred at room temperature for 20 hours, then the mixture of reaction was concentrated. 100 ml of NaHCO solution; saturated were added to the residue, and the mixture was stirred at room temperature for 1 hour. The crystalline product was filtered, washed with water, and dried. Thus, 4.71 g (90%) of the title product was obtained. MS (ESI) m/z 333.1 (M+Na)*.

Intermediate 4 (tert-butyl 7-chloro-2-thioxO-2,3,4,5-tetrahydro-1H-1-benzazepin-4-iDcarbamate

No

[00403] A mixture of 2.35 g (7.56 mmol) of (7-chloro-2-0x0-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate of tert-butyl (Intermediate 3), 65 mL of pyridine and 3.98 g (9.84 mmol) of Lawesson's reagent was stirred at 120°C for 4 hours, then the reaction mixture was concentrated. 100 ml of NaHCO solution; saturated were added to the residue and the mixture was stirred at room temperature for 1 hour. The crystalline product was filtered, washed with water, and dried. Thus, 2.32 g (94%) of the title product was obtained. MS (ESI) m/z 327.2 (M+H)*.

Intermediate 5 tert-Butyl T-chloro-2-(methylsulfanyl)-4,5-dihydro-3H-1-benzazepin-4-ylcarbamate No

[00404] A mixture of 2.32 g (7.1 mmol) of (7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate of fert-butyl (Intermediate 4), 140 mL of acetone, 1.96 g (14.2 mmol) of KxCO; and 1.33 mL (21.4 mmol) of iodomethane was stirred at room temperature for 20 hours. The reaction mixture was concentrated, water was added to the residue and extracted with ethyl acetate, the organic phase was dried over Na 7 SO, anhydrous, filtered, and concentrated. Thus, 2.04 g (84%) of the title product was obtained. MS (ESI) m/z 341.2 (M+H)*.

Intermediate 6 (S-methoxy-?-nitrophenyl) ethyl acetate

[00405] To a mixture of 10.18 g (90.7 mmol) of potassium tert-butoxide and 90 ml of dry DMF, a mixture of 3.86 ml (36.3 mmol) of ethyl chloroacetate, 5, 56 g (36.3 mmol) of 4-nitroanisole (Merck) and 40 mL of dry DMF were added dropwise at 0°C under nitrogen. The resulting dark purple reaction mixture was stirred at 0°C for 2.5 hours, then 35 mL of 3N hydrochloric acid was added dropwise and diluted with water. The mixture was extracted twice with ethyl acetate, the combined organic phases were washed with aqueous NaCl, dried over anhydrous Na 7 SO, filtered and concentrated. Thus, 7.33 g (84%) of the title product was obtained as a brown oil. MS (ESI) m/z 240.2 (M+H)*.

Intermediate 7 acid (S-methoxy-2-nitropheniDacetic Lo

[00406] A mixture of 7.33 g (30.6 mmol) of ethyl (5-methoxy-2-nitrophenyl)acetate (Intermediate 6), 1.54 g (36.8 mmol) of lithium hydroxide monohydrate, 90 ml of THF and 45 ml of water were stirred at room temperature for 16 hours. The organic solvent was evaporated and the

The residue was extracted with ethyl acetate. 40 ml of 1N hydrochloric acid were added to the aqueous phase, extracted twice with ethyl acetate, the combined organic phases were dried over anhydrous Na7SO, filtered and concentrated. Thus, 2.27 g (35%) of the title product was obtained. MS (ESD m/z 229.1 (M+NH3 )*. Intermediate 8 5-[1-Hydroxy-2-(5-methoxy-2-nitrophenyethylidene]-2,2-dimethyl-1,3-dioxane- 4,6-dione the NO, to the E Ove

[00407] To a mixture of 2.27 g (10.7 mmol) of (5-methoxy-2-nitrophenyl)acetic acid (Intermediate 7), 40 mL of dry acetonitrile, 1.70 g (11.8 mmol) of Meldrum's acid, 131 mg (1.07 mmol) of DMAP and 4.21 mL (24.2 mmol) of DIPEA, 1.46 mL (11.8 mmol) of trimethylacetyl chloride was added dropwise and the mixture of reaction was stirred at 40°C for 4 hours. The mixture was cooled to 0°C, 26 ml of 1N hydrochloric acid were added dropwise and diluted with 60 ml of water. The precipitated product was filtered, washed with water and dried over phosphorus pentoxide in a vacuum desiccator. Thus, 2.45 g (68%) of the title product was obtained which was used without further purification. Intermediate 9 Methyl 4-(S-methoxy-2-nitrophenyl)-3-oxobutanoate SO" OMe

[00408] A mixture of 245 g (7.26 mmol) of 5-[1-hydroxy-2-(5-methoxy-2-nitrophenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4, 6-dione (Intermediate 8), 10 ml of methanol and 30 ml of toluene was stirred at 115°C for 1.5 hours. The mixture was cooled to room temperature, acetate

134 / 323 ethyl and aqueous NaCl were added. The phases were separated, the organic phase was dried over anhydrous Na7SO, filtered and concentrated. Cyclohexane was added to the residue, stirred for 1 hour and the product filtered. Thus, 1.85 g (95%) of the title product was obtained. MS (ESI) m/z 268.2 (M+H)*.

Intermediate 10 Methyl 3-amino-4(S-methoxy-2-nitrophenyl)but-2-enoate

NH Ove

[00409] A mixture of 1.07 g (4 mmol) of methyl 4-(5-methoxy-2-nitrophenyl)-3-oxobutanoate (Intermediate 9), 20 mL of methanol and 6.17 g (80 mmol) ammonium acetate solution was stirred at room temperature for 16 hours. The mixture was diluted with water, stirred for 1 hour, and the product was filtered. Thus, 0.92 g (86%) of the title product was obtained which was used without further purification.

Intermediate 11 Methyl 3-amino-4-(5-methoxy-2-nitrophenyl)butanoate

The OMe

[00410] To 9 mL of acetic acid, 0.67 g (17.8 mmol) of NaBH was added over 45 minutes while maintaining the temperature around 10°C. 0.79 g (3 mmol) of methyl 3-amino-4-(5-methoxy-2-nitrophenyl)but-2-enoate (Intermediate 10) was added to the resulting mixture and stirred at room temperature for 1.5 hours. . The mixture was diluted with water during cooling, then basified with K3CO; solid and extracted twice with ethyl acetate. The combined organic phases were washed with aqueous KCO; and then with aqueous NaCl solution, dried over anhydrous Na7SO, filtered and concentrated. Thus, 0.69 g (87%) of the product

135 / 323 holder was obtained. MS (ESI) m/z 269.2 (M+H)*.

Intermediate 12 Methyl 3-[(fert-butoxycarbonyl)amino]-4-(S-methoxy-2-nitrophenylbutanoate Y.'cooMe

[00411] To a mixture of 0.69 g (2.6 mmol) of methyl 3-amino-4-(5-methoxy-2-nitrophenyl)butanoate (Intermediate 11), 20 mL of methanol and 0.7 g (3.22 mmol) di-tert-butyl dicarbonate, 0.43 g (5.14 mmol) of NaHCO; was added at 10°C. The reaction mixture was stirred at room temperature for 1.5 hours, diluted with water, and the precipitated product was filtered. Thus, 0.72 g (76%) of the title product was obtained. MS (ESI) m/z 391.1 (M+Na)”.

Intermediate 13 Methyl 4-(2-amino-5-methoxyphenyl)-3-[(fert-butoxycarbonyl)aminobutanoate Y.'cooMe

[00412] 0.72 g (2 mmol) of methyl 3-[(fert-butoxycarbonyl)Jamino]-4-(5-methoxy-2-nitrophenyl)butanoate (Intermediate 12) in 50 mL of methanol was hydrogenated in the presence of 80 mg of 10% Pd/C at room temperature under atmospheric pressure. After filtering off the catalyst, the filtrate was concentrated to give 0.62 g (94%) of the title product. MS (ESI) m/z 339.3 (M+H)*.

Intermediate 14 (fert-butyl 7-methoxy-2-0Xx0-2,3,4,5-tetrahydro-1H-1-benzazepin-4-iDcarbamate

136 / 323 meo NHBoc

[00413] 0.56 g (1/7 mmol) of methyl 4-(2-amino-S-methoxyphenyl)-3-[(tert-butoxycarbonyl)amino]-butanoate (Intermediate 13) was dissolved in 12 mL of methanol and 0.26 mL of 30% methanolic sodium methoxide solution was added, and the mixture was stirred at room temperature for 20 hours. 1.7 mL of 1N hydrochloric acid was added to the mixture on cooling, diluted with water, and the resulting precipitate was filtered, washed with water and dried over phosphorus pentoxide in a vacuum desiccator. Thus, 0.4 g (80%) of the title product was obtained. MS (ESI) m/z 329.2 (M+Na)*.

Intermediate 15 (tert-butyl 7-methoxy-2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-iDcarbamate

No

[00414] A mixture of 0.44 g (14 mmol) of tert. butyl (Intermediate 14), 20 mL of pyridine and 1.34 g (3.3 mmol) of Lawesson's reagent was stirred at 120 °C for 4.5 hours The reaction mixture was cooled to room temperature, diluted with ethyl acetate , and washed twice with 5% NaHCO3 solution. The organic phase was dried over anhydrous Na 2 SO, filtered and concentrated. Diethyl ether was added to the residue and the precipitated solid was filtered off after 1 hour of stirring. The crude product was recrystallized from 7 ml of ethanol to give 0.15 g (32%) of the title product MS (ESD m/z 345.2 (M+Na)*.

Intermediate 16 5-[1-hydroxy-2-(5-methyl-2-nitrophenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione

137 /323 NO, Oo + OH o

[00415] The title product was prepared from 2-(5-methyl-2-nitrophenyl)acetic acid (Astatech Inc.) according to the method described for Intermediate 8 and was used without further purification. Intermediate 17 Methyl 4-(5-methyl-2-nitrophenyl)-3-oxobutanoate

ST

[00416] The title product was prepared from 5-[1-hydroxy-2-(5-methyl-2-nitrophenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione ( Intermediate 16) according to the method described for Intermediate 9 and was used without further purification. Intermediate 18 Methyl 3-amino-4-(5-methyl-2-nitrophenyl)but-2-enoate NO? ZA >cooMe NH;

[00417] The title product was prepared from methyl 4-(5-methyl-2-nitrophenyl)-3-oxobutanoate (Intermediate 17) according to the method described for Intermediate 10 and was used without further purification. Intermediate 19 Methyl 3-amino-4-(5-methyl-2-nitrophenyl)butanoate NO? COOoMe NH2

[00418] The title product was prepared from methyl 3-amino-4-(5-methyl-2-nitrophenyl)but-2-enoate (Intermediate 18) according to the method described for Intermediate 11 and was used without another purification.

138 /323 Intermediate 20 Methyl 3-[(fert-butoxycarbonyl)amino]-4-(5-methyl-2-nitrophenyl)butanoate LL NHBoc

OT

[00419] The title product was prepared from methyl 3-amino-4-(5-methyl-2-nitrophenyl)butanoate (Intermediate 19) according to the method described for Intermediate 12 and was used without further purification.

Intermediate 21 Methyl 4-(2-amino-5-methyl-phenyl)-3-[(fert-butoxycarbonyl)amino]butanoate K NHBoc

OT

[00420] The title product was prepared from methyl 3-[(tert-butoxycarbonyl)amino]-4-(5-methyl-2-nitrophenyl)butanoate (Intermediate 20) according to the method described for Intermediate 13 and was used without further purification.

Intermediate 22 (tert-butyl 7-methyl-2-OxO-2,3,4,5-tetrahydro-1H-1-benzazepin-4-iDcarbamate

No

[00421] The title product was prepared from methyl 4-(2-amino-5-methyl-phenyl)-3-[(tert-butoxycarbonyl)]amino]butanoate (Intermediate 21) according to the method described for Intermediate 14. MS (ESI) m/z 313.1 (M+Na)*.

Intermediate 23 (7-methyl-2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-

139 / 323 tert-butyl iDcarbamate

No

[00422] A mixture of 0.71 g (2.4 mmol) of (7-methyl-2-OxO-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate of tert-butyl (Intermediate 22), mL of dry THF and 0.59 g (1.A7 mmol) of Lawesson's reagent was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was purified by column chromatography using cyclohexane:ethyl acetate=80:20 as eluent to give 0.42 g (56%) of the title product. MS (ESD m/z 307 (M+H)*.

Intermediate 24 (5-bromo-2-nitrophenyl)ethyl acetate 2

[00423] The title product was prepared from d4-nitro-bromobenzene (Combi-Blocks Inc.) according to the method described for Intermediate 6. MS (ESI) m/z 305.1 (M+NH3 )* .

Intermediate 25 (5-bromo-2-nitrophenyl)acetic acid 2

[00424] The title product was prepared from ethyl (5-bromo-2-nitrophenyl)acetate (Intermediate 24) according to the method described for Intermediate 7 and was used without further purification.

Intermediate 26 5-[1-hydroxy-2-(5-bromo-2-nitropheniD)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione | The

ER o Br

140 / 323

[00425] The title product was prepared from (5-bromo-2-nitrophenyl) acetic acid (Intermediate 25) according to the method described for Intermediate 8 and was used without further purification. Intermediate 27 Methyl 4-S-bromo-2-nitrophenyl)-3-oxobutanoate Br

[00426] The title product was prepared from 5-[1-hydroxy-2-(5-bromo-2-nitrophenyl)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione ( Intermediate 26) according to the method described for Intermediate 9. MS (ESD m/z 335.0 (M+NH3 )*. Intermediate 28 3-amino-4-(S-bromo-2-nitrophenyl)but-2 -methyl enoate NH?Br

[00427] The title product was prepared from methyl 4-(5-bromo-2-nitrophenyl)-3-oxobutanoate (Intermediate 27) according to the method described for Intermediate 10 and was used without further purification. Intermediate 29 3-amino-4| Methyl 5-bromo-2-nitrophenyl)butanoate NHAz Br

[00428] The title product was prepared from methyl 3-amino-4-(5-bromo-2-nitrophenyl)but-2-enoate (Intermediate 28) according to the method described for Intermediate 11. MS (ESI ) m/z 319.0 (M+H)*. Intermediate 30 Methyl 3-[(fert-butoxycarbonyl)amino]-4-(5-bromo-2-nitrophenyl)butanoate

141 /323 Y 'cooMe

[00429] The title product was prepared from methyl 3-amino-4-(5-bromo-2-nitrophenyl)butanoate (Intermediate 29) according to the method described for Intermediate 12. MS (ESI) m/z 439.1 (M+Na)*.

Intermediate 31 Methyl 4-(2-amino-5-bromo-phenyl)-3-[(fert-butoxycarbonyl)amino]butanoate Y cooMe

[00430] 245 g (5.87 mmol) of methyl 3-[(tert-butoxycarbonyl)Jamino]-4-(5-bromo-2-nitrophenyl)butanoate (Intermediate 30) in 200 mL of toluene were hydrogenated at room temperature. ambient under atmospheric pressure in the presence of 0.25 g of 5% Pt/C catalyst. After filtering the catalyst, the filtrate was concentrated to give 2.15 g (94%) of the title product. MS (ESD) m/z 409.1 (M+Na)*.

Intermediate 32 (fert-butyl 7-bromo-2-0x0-2,3,4,5-tetrahydro-1H-1-benzazepin-4-iDcarbamate

No

[00431] To a mixture of 2.15 g (5.55 mmol) of methyl 4-(2-amino-5-bromo-phenyl)-3-[(tert-butoxycarbonyl)amino]butanoate (Intermediate 31) and 60 mL dry THF 0.69 g (6.11 mmol), potassium tert-butoxide was added under nitrogen at 0°C for 30 minutes and the reaction mixture was stirred at room temperature for 3 hours. Dry ice was then added and then the mixture was diluted with ethyl acetate and water. The phases were separated, the aqueous phase was extracted with ethyl acetate, the phases

The combined organics were washed with aqueous NaCl solution, dried over anhydrous NaSO, filtered and concentrated. Diethyl ether was added to the crude product, stirred for 1 hour at room temperature, filtered and washed with diethyl ether. Thus, 0.83 g (42%) of the title product was obtained. MS (ESD m/z 409.1 (M+Na)*.

Intermediate 33 (fer-butyl 7-bromo-2-thioxO-2,3,4,5-tetrahydro-1H-1-benzazepin-4-iDcarbamate

No

[00432] A mixture of 0.83 g (2.3 mmol) of (7-bromo-2-Ox0-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate of tert-butyl (Intermediate 32), 28 mL of dry THF and 0.57 g (1.4 mmol) of Lawesson's reagent was stirred at room temperature for 16 hours. The solvent was evaporated, diethyl ether was added to the residue and the precipitated solid was filtered off after 1 hour of stirring. Thus, 0.79 g (91%) of the title product was obtained. MS (ESI) m/z 371 (M+H)*.

Intermediate 34 Methyl 2-(S-bromo-2-nitrobenzyl)-1,3-dioxolan-2-ylJacetate NO? Fe Ew

[00433] A mixture of 3.28 g (104 mmol) of methyl 4-(5-bromo-2-nitrophenyl)-3-oxobutanoate (Intermediate 27), 1.7 mL of methanol, 118 mg (0.6 mmol) of p-toluenesulfonic acid monohydrate, 5.68 mL (52 mmol) of trimethyl orthoformate and 11.6 mL (207 mmol) of ethylene glycol was stirred at 50°C for 96 hours. KxCO aqueous solution; was added to the reaction mixture, then extracted twice with ethyl acetate. The organic phases were dried over anhydrous Na72SO4, filtered and concentrated. THE

The residue was purified by column chromatography using cyclohexane:ethyl acetate=80:20 as eluent. Thus, 2.29 g (61%) of the title product was obtained. MS (EST) m/z 379.1 (M+NH2 )*.

Intermediate 35 2-(2-Amino-5-bromobenzyl)-1,3-dioxolan-2-yl Jacetate — Methyl NH?

LO

[00434] 2.29 g (6.4 mmol) of methyl [2-(5-bromo-2-nitrobenzyl)-1,3-dioxolan-2-yl]acetate (Intermediate 34) in 200 mL of toluene was hydrogenated in room temperature under atmospheric pressure in the presence of f 0.56 g of 5% Pt/C catalyst. After filtering the catalyst, the filtrate was concentrated to give 2.1 g (100%) of the title product. MS (ESI) m/z 330.0 (M+H)*.

Intermediate 36 T-bromo-1,5-dihydrospiro[1-benzazepine-4.2"-1,3]dioxolane]-2(3HD)-one

No

[00435] The title product was prepared from methyl [2-(2-amino-5-bromobenzyl)-1,3-dioxolan-2-yl]acetate (Intermediate 35) according to the method described for Intermediate 32. MS (ESI) m/z 300.0 (M+H)*.

Intermediate 37 2-nitro-5-(trifluoromethyl))phenyl Ethyl jacetate : F COOEt

[00436] 7AS g (66.555 mmol) potassium tert-butoxide was added to 75 mL of DMF under stirring and argon. The mixture was cooled

144 / 323 at 000°C and a solution of 5.00 g (26.16 mmol) of 1-nitro-4-(trifluoromethyl)benzene (Apollo Scientific Ltd.) and 2.98 mL (28.00 mmol) of ethyl ester of chloroacetic acid in 25 ml of DMF was added dropwise. A dark purple reaction mixture was obtained which was stirred at 0°C for 1.5 hours. Under cooling with ice water, 5% hydrochloric acid was added to the reaction mixture until the pH of the solution was about 3. As a result of acidification, the color of the solution turned yellow. The reaction mixture was extracted with 3x50 mL of ethyl acetate and the combined organic phases were washed with NaHCO solution; saturated solution and saturated NaCl solution. The solution was dried over MgSO₄, filtered and concentrated. Thus, 6.86 g (95%) of the title product was obtained as an orange oil. MS (ESID) m/z 278.2 (M+H)*. Intermediate 38 2-nitro-S-(trifluoromethyl]phenyljacetic acid

[00437] 6.85 g (24.71 mmol) of [2-nitro-5-(trifluoromethyl)phenyl Ethyl jacetate (Intermediate 37) was dissolved in a mixture of 100 ml of THF, 50 ml of methanol and 50 ml of Water. 5.18 g (123.45 mmol) of lithium hydroxide monohydrate was added to the orange solution and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and after dilution with water the pH was adjusted to about 4-5 with 1N hydrochloric acid. The orange precipitate appeared and was filtered (the starting material from the previous step, 1-nitro-4-(trifluoromethyl)benzene). Another acidification (pH = 2) resulted in another precipitation (expected product), so the suspension was cooled in an ice-water bath, the yellow crystalline material was filtered and washed with a little water. The acidic aqueous phase was extracted twice with 30 ml of ethyl acetate, the combined organic phases were washed with saturated NaCl solution, dried over

145 /323 MgSO4 , filtered and concentrated. The yellow product was dried in a drying oven. Thus, 4.88 g (79%) of the title product was obtained as a yellow powder. MS (EST) m/z does not ionize.

Intermediate 39 S-(1-hydroxy-2-[2-nitro-S-(trifluoromethyl-phenylethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione Oo On om O For

[00438] 4.79 g (19.23 mmol) of [2-nitro-5-(trifluoromethyl)phenyl]acetic acid (Intermediate 38) was dissolved in 250 mL of acetonitrile. 7.54 mL (43.30 mmol) of DIPEA, 3.05 g (21.20 mmol) of Meldrum's acid and 0.24 g (1.92 mmol) of DMAP were added to the solution. With moderate stirring and measuring the temperature of the solution, 2.61 mL (21.20 mmol) of trimethylacetyl chloride was added dropwise in such a way that the temperature of the mixture did not exceed 30°C. The reaction mixture was then stirred at 40°C for 4 hours. The solution was cooled in an ice-water bath and the pH adjusted to acid by the addition of 90 mL of 1W hydrochloric acid. After adding another 90 mL of water, large precipitation occurred which was filtered, washed with mother liquor and then with water. The product was dried in vacuo using phosphorus pentoxide at room temperature. Thus, 6.02 g (83%) of the title product was obtained as a white powder. MS (ESI) m/z decomposes.

Intermediate 40 Methyl 4-[2-nitro-5-(trifluoromethyl]phenyl]-3-oxobutanoate

FF IT'S

[00439] 5.11 g (1360 mmol) of 5-(1-hydroxy-2-[2-nitro-5-

146 / 323 (Trifluoromethyl)phenyl Jetylidene )-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 39) were dissolved in a mixture of 68 ml of methanol and 264 ml of toluene, and the mixture reaction mixture was stirred at 110°C for 3 hours. After cooling to room temperature, 130 mL of saturated NaCl solution and 100 mL of ethyl acetate were poured into the solution. The phases were separated and the organic phase was dried over MgSO4 , filtered and concentrated. Thus, 4.09 g (98%) of the title product was obtained as a yellow waxy material. MS (ESI) m/z 306.1 (M+H)+; 323.1 (M+NH3 )*.

Intermediate 41 Methyl 12-[2-nitro-5-(trifluoromethyl)benzyl]-1,3-dioxolan-2-ylJacetate

[00440] To a mixture of 4.87 g (15.95 mmol) of methyl 4-[2-nitro-5-(trifluoromethyl)phenyl]-3-oxobutanoate (Intermediate 40), 2.46 mL (60, 80 mmol) of methanol, 15.00 mL (268.00 mmol) of ethylene glycol, and 7.49 mL (68.50 mmol) of trimethyl orthoformate, 0.18 g (0.94 mmol) p-toluenesulfonic acid monohydrate was added. The reaction mixture was stirred at 50°C for 72 hours, then cooled and 70 mL of NaCO solution; saturated solution and 70 mL of water were added, which resulted in a highly precipitated mixture. The mixture was extracted twice with 100 ml of ethyl acetate and the combined organic phases were washed with saturated NaCl solution. After drying over MgSO4, it was filtered and concentrated. The residue was purified by column chromatography using cyclohexane:ethyl acetate=4:1 as eluent. Thus, 2.75 g (49%) of the title product was obtained as a pale yellow oil. MS (ESI) m/z 316.1 (M+H)+; 367.1 (M+NH3 )*.

Intermediate 42 [2-[2-amino-5-(trifluoromethyl)benzyl]-1,3-dioxolan-2-

147 /323 methyl ylacetate w =

[00441] 2.19 g (6.27 mmol) of methyl (2-[2-nitro-5-(trifluoromethyl)benzyl]-1,3-dioxolan-2-yl)acetate (Intermediate 41) in 50 mL of toluene were hydrogenated at room temperature under atmospheric pressure in the presence of 0.219 g of 5% Pt/C catalyst. After filtering the catalyst, the filtrate was concentrated to give 2.00 g (100%) of the title product as a light orange oil. MS (ESI) m/z 320.2 (M+H)*.

Intermediate 43 T-(trifluoromethyl)-1,5-dihydrospiro[1-benzazepine-4.2"-1,3]dioxolane]-2(3H -one

[00442] 2.00 g (6.3 mmol) of methyl (2-[2-amino-5-(trifluoromethyl)benzyl]-1,3-dioxolan-2-yl)acetate (Intermediate 42) was dissolved in 70 mL of dry THF, then under argon the solution was cooled to 0°C and 0.78 g (6.91 mmol) of potassium tert-butoxide was added. The dark colored solution was stirred at room temperature for 4 hours, then dry ice was added to the reaction mixture. The solution was concentrated and the residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent. Thus, 1.05 g (58%) of the title product was obtained as a white powder. MS (ESI) m/z 288.1 (M+H)*.

Intermediate 44 Methyl 3-amino-4-[2-nitro-S-(trifluoromethyl)phenylbutanoate hydrochloride

148 / 323 a) Methyl 3-amino-4-2-nitro-5-trifluoromethyl)phenyl]but-2-enoate

[00443] 1.00 g (3.3 mmol) of methyl 4-[2-nitro-5-(trifluoromethyl)phenyl]-3-oxobutanoate (Intermediate 40) was dissolved in 30 mL of methanol and 2.78 g (36.0 mmol) of ammonium acetate was added. The reaction mixture was stirred at room temperature for 72 hours. 150 mL of water was added to the light brown solution and extracted twice with 70 mL of ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried over MgSO 3 , filtered and concentrated, then dried over phosphorous pentoxide in a desiccator. Thus, 0.96 g (96%) of the title product was obtained. b) Methyl 3-amino-4-[2-nitro-5-(trifluoromethyl)phenyl-butanoate hydrochloride

[00444] 2.00 g (9.4 mmol) of NaBH(OAc);3 was added to 15 mL of glacial acetic acid at 10°C under aqueous cooling. A mixture of 0.96 g (3.2 mmol) of methyl 3-amino-4-[2-nitro-5-(trifluoromethyl)phenyl Ibut-2-enoate in 5 ml of glacial acetic acid was added dropwise to the solution obtained above, and the reaction mixture was stirred at room temperature for 2 hours. Then, under cooling with ice water, 50 mL of water and 50 mL of 30% NaOH solution were added to the reaction mixture. The pH was adjusted to approximately 8 with NaHCO solution; saturated and extracted twice with 70 ml of ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried over MgSO, and filtered. The calculated amount of 2.5M hydrogen chloride solution in ethyl acetate solution was added to the filtered ethyl acetate solution, and the mixture was concentrated. The residue was crystallized by titration with diisopropyl ether. Thus, 0.78 g (72%) of the title product was obtained as a white powder. MS (ESI) m/z 307.1 (M+H)*.

149 / 323 Intermediate 45 Methyl 3-[(fert-butoxycarbonyl)amino]-4-[2-nitro-5-(trifluoromethyl)phenyl-butanoate LL NHBoc f

[00445] 0.78 g (2.3 mmol) of methyl 3-amino-4-[2-nitro-5-(trifluoromethyl)phenyl-butanoate hydrochloride (Intermediate 44) was dissolved in mL of methanol. 0.77 g (9.10 mmol) of NaHCO; was added to the solution thus obtained and 0.62 g (2.85 mmol) of di-tert-butyl dicarbonate was added to the suspension under ice-cooling and stirring, then the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. During the work, 100 mL of water was poured into the mixture, then the precipitated material was filtered, washed with water, and dried. Thus, 0.88 g (72%) of the title product was obtained as a white powder. MS (ESI) m/z 429.2 (M+Na)*.

Intermediate 46 3-[(fert-butoxycarbonyl)amino]-4-[2-nitro-5-(trifluoromethyl)phenylbutanoic acid

[00446] The title product was prepared from methyl 3-[(tert-butoxycarbonyl)amino]-4-[2-nitro-5-(trifluoromethyl)phenyl-butanoate (Intermediate 45) according to the method described in step £) of Method B) of Intermediate 1. MS (ESD) m/z 415.1 (M+Na)*.

Intermediate 47 4-[2-amino-5-(trifluoromethyl)phenyl]-3-[(tert-butoxycarbonylamino]butanoic acid

150 /323

[00447] The title product was prepared from 3-[(tert-butoxycarbonyl)amino]-4-[2-nitro-5-(trifluoromethyl)phenyl-butanoic acid (Intermediate 46) according to the method described for Intermediate 42 MS (ESD m/z 385.2 (M+Na)*.

Intermediate 48 tert-Butyl 2-OxO-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl carbamate

[00448] A mixture of 0.60 g (1.7 mmol) of 4-[2-amino-5-(trifluoromethyl)phenyl]-3-[(tert-butoxycarbonyl Jamino]butanoic acid (Intermediate 47), 20 mL of DMF, 0.60 mL (3.39 mmol) of DIPEA, 0.30 g (1.99 mmol) of HOBt and 0.38 g (1.99 mmol) of EDC was stirred at room temperature for 16 hours and 30 mL of saturated NaHCO2 solution was poured into the residue and after a short stirring the precipitated material was filtered, washed with water, and dried. Thus, 0.49 g (87%) of the title product was obtained as a powder brown MS (ESI) m/z 367.1 (M+H)*.

Intermediate 49 tert-Butyl 2-thioxo-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl carbamate

[00449] A mixture of 046 g (1.3 mmol) of [2-OxO-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl]carbamate of tert-butyl (Intermediate 48), 10 ml of pyridine and 0.70 g (1.7 mmol) of Lawesson's reagent was stirred at 120°C for 3 hours. The reaction mixture was

151 /323 concentrated and stirred at room temperature for 12 hours after adding 10 ml of water and 20 ml of NaHCO solution; saturated. The precipitated material was filtered, washed with water, and dried. Thus, 0.44 g (92%) of the title product was obtained as a brown powder which was used without further purification.

Intermediate 50 tert-Butyl 2-(methylsulfanyl)-7-(trifluoromethyl)-4,5-dihydro-3H-1-benzazepin-4-yl carbamate

[00450] 0.44 g (1.2 mmol) tert-butyl [2-thioxo-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl]carbamate (Intermediate 49) was dissolved in 30 mL of acetone, and 0.34 g (244 mmol) of K3CO; was added. 0.23 mL (3.7 mmol) of iodomethane was added dropwise to the reaction mixture and stirred at room temperature for 24 hours. 20 mL of ethyl acetate was poured into the reaction mixture and the organic phase was washed first with water, then with saturated NaCl solution, dried over MgSO₄, filtered and concentrated. Thus, 0.46 g (100%) of the title product was obtained as an orange powder. MS (ESI) m/z 375.1 (M+H)*.

Intermediate 51 Methyl 2-(S-chloro-2-nitrobenzyl)-1,3-dioxolan-2-yl acetate No;

[00451] The title product was prepared from methyl 4-(5-chloro-2-nitrophenyl)-3-oxobutanoate (step b) of Method B) of Intermediate 1) according to the method described for Intermediate 41. MS (ESID) m/z 316.1 (M+H)+; 333.1 (M+NH2)*.

Intermediate 52

2-(2-Amino-5-chlorobenzyl)-1,3-dioxolan-2-ylJacetate from "

[00452] The title product was prepared from [2-(5-chloro-2-nitrobenzyl)-1,3-dioxolan-2-yl Methyl jacetate (Intermediate 51) according to the method described for Intermediate 42. MS (ESI) m/z 286.1 (M+H)*.

Intermediate 53 T-Chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3 dioxolane -263H)-one o

[00453] The title product was prepared from [2-(2-amino-5-chlorobenzyl)-1,3-dioxolan-2-yl Methyl jacetate (Intermediate 52) according to the method described for Intermediate 43. MS (ESI) m/z 254.1 (M+H)*.

Intermediate 54 fert-butyl 2-([trans-4-(trifluoromethyl)cyclohexyl]carbonyl)hydrazine carboxylate

[00454] 2.13 g (10.9 mmol) of trans-4-(trifluoromethyl)cyclohexane carboxylic acid (Manchester Organics Ltd.) was dissolved in 50 mL of DMF. 1.44 g (10.9 mmol) of tert-butylhydrazine carboxylate, 4.75 mL (27.3 mmol) of DIPEA, 2.00 g (13.10 mmol) of HOBt and 2.51 g (13. 1 mmol) of EDC was added to the solution. The reaction mixture was stirred at room temperature for 36 hours, then concentrated. 40 ml of NaHCO solution; was added to the residue and after a short stirring the precipitate was filtered, washed with water and dried in a vacuum oven over phosphorus pentoxide. Thus, 3.35 g (99%) of the title product was obtained as a white powder. GC-MS (EI) m/z 310.1.

153 /323 Intermediate 55 frans-4-(trifluoromethyl)cyclohexanecarboxylic acid hydrazide TOR”

[00455] 3.35 g (10.8 mmol) of tert-butyl 2-([trans-4-(trifluoromethyl)cyclohexyl]carbonyl Yhydrazine carboxylate (Intermediate 54) was dissolved in a mixture of 50 mL of acetate of ethyl and 20 mL of ethanol, then 30 mL of a 2.5M solution of hydrogen chloride in ethyl acetate were added. The reaction mixture was stirred at room temperature for 16 hours, then 150 mL of diethyl ether was added and cooled in an ice-water bath. The precipitated product was filtered and washed with diethyl ether. The filtered material was stirred with 100 mL of NaHCO solution; saturated (pH - 8), filtered, washed with water, and dried in an oven at Vacuum over phosphorus pentoxide Thus 1.77 g (78%) of the title product was obtained as a white powder GC-MS (EI) m/z 210.1 Intermediate 56 2-[(3,3-difluorocyclobutyl)carbonyl tert-butyl]hydrazine carboxylate:

F

[00456] The title product was prepared from 3,3-difluorocyclobutane carboxylic acid (Combi-Blocks Inc.) according to the method described for Intermediate 54. GC-MS (EI) m/z 250.1.

Intermediate 57 3,3-difluorocyclobutane carboxylic acid hydrazide

[00457] The title product was prepared from ferc-butyl 2-[(3,3-difluorocyclobutyl Jcarbonyl Jhydrazine carboxylate (Intermediate

154 / 323 56) according to the method described for Intermediate 55. GC-MS (ED) m/z 150.1.

Intermediate 58 + Methyl S-chloro-2-nitrophenyl)-3-hydroxybutanoate

[00458] 3.13 g (11.5 mmol) of methyl 4-(5-chloro-2-nitrophenyl)-3-oxobutanoate (step b) of Method B) of Intermediate 1) was dissolved in 100 mL of methanol , the solution was cooled to 0°C, and 0.48 g (12.6 mmol) of NaBH was added to the reaction mixture. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and 100 ml of water was added to the residue, the pH of the solution was adjusted to about 7 with 5% hydrochloric acid. The aqueous phase was extracted with diethyl ether, the organic phase was dried over MgSO4 , filtered and concentrated. Thus, 2.85 g (90%) of the title product was obtained which was used without further purification in the next step.

Intermediate 59 Methyl 3-[[tert-butyl(dimethylD)silyl Joxy |-4-(5-chloro-2-nitrophenyl)butanoate

OC

[00459] 136 g (50 mmol) of methyl 4-(5-chloro-2-nitrophenyl)-3-hydroxybutanoate (Intermediate 58) was dissolved in 15 mL of DMF, then 0.85 g (124 mmol) of 1H -imidazole and 0.90 g (6.0 mmol) of fert-butyl dimethylchlorosilane was added. The solution was stirred at room temperature for 24 hours. The reaction mixture was poured into water and the product was extracted twice with 50 ml of ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried over MgSO4 , filtered and concentrated. The residue was purified by

155/323 column chromatography using n-hexane:ethyl acetate=4:1 as eluent. Fractions containing the expected product were concentrated to give 1.70 g (88%) of the title product. MS (ESI) m/z 388.2 (M+H)*.

Intermediate 60 3-f[tert-butyl(dimethylsilyljoxy)-4-(5-chloro-2-nitrophenyl)butanoic acid v

CI

[00460] The title product was prepared from methyl 3-([tert-butyl(dimethyl)silylJoxy)-4-(5-chloro-2-nitrophenyl)butanoate (Intermediate 59) according to the method described for Intermediate 38. MS (EST) m/z 374.2 (M+H)*.

Intermediate 61 4-(2-amino-5-chlorophenyl)-3-([tert-butyl(dimethyl)silyl JoxyY butanoic acid

OC

[00461] The title product was prepared from 3-([tert-butyl(dimethyl)silylJoxy)-4-(5-chloro-2-nitrophenyl)butanoic acid (Intermediate 60) according to the method described for Intermediate 42. MS (ESI) m/z 344.2 (M+H)*.

Intermediate 62 4-f[tert-butyl(dimethylsilylJoxy)-7-chloro-1,3,4,5-tetrahydro-2H-1-benzazepine-2-one o

NO +

THE

[00462] The title product was prepared from 4-(2-amino-5-chlorophenyl)-3-([tert-butyl(dimethyl)silylJoxy)butanoic acid (Intermediate 61) according to the method described for Intermediate 48. MS (ESI) m/z 326.2

156 /323 (M+H)*.

Intermediate 63 4-f([tert-butyl(dimethyl-silyl]oxy-7-chloro-1,3,4,5-tetrahydro-2I1-1-benzazepine-2-thione

NO HERE +

THE

[00463] The title product was prepared from 4-([tert-butyl(dimethyl)silylJoxy)-7-chloro-1,3,4,5-tetrahydro-2H-1-benzazepine-2-one (Intermediate 62) according to the method described for Intermediate 49. MS (ESD m/z 342.1 (M+H)*.

Intermediate 64 trans-4-(piperidin-1-ylmethylcyclohexane — carboxylate — methyl

[00464] 0.30 g (1.8 mmol) of methyl trans-4-formylcyclohexane carboxylate (Synthonix) was dissolved in 10 mL of 1,2-dichloroethane, and 0.52 mL (5.3 mmol) piperidine and 0.19 mL (3.4 mmol) acetic acid were added to the solution. The resulting mixture was cooled to 0°C and 1.16 g (5.5 mmol) of NaBH(OAc); was added, and the mixture was stirred at room temperature for 16 hours. Then, 30 mL of water was added to the reaction mixture and the pH of the mixture was adjusted to about 9 with NaxCO3 solution. The mixture was extracted twice with 20 ml of dichloromethane, the combined organic phases were dried over anhydrous MgSO, filtered and concentrated. Thus, 0.40 g (95%) of the title product was obtained which was used without further purification.

Intermediate 65 trans -4-(piperidin-1-ylmethyl)cyclohexane carboxylic acid hydrazide

157 /323 On OS

[00465] 0.40 g (1.7 mmol) of methyl trans-4-(piperidin-1-ylmethyl)cyclohexane carboxylate (Intermediate 64) was dissolved in 5 mL of methanol, and the solution was poured into a pressure resistant glass reactor. 5 ml (100 mmol) of hydrazine hydrate was added and the reaction mixture was stirred at 75°C for 16 hours. The reaction mixture was concentrated and cyclohexane and anhydrous toluene were evaporated from the residue. Thus, 0.39 g (97%) of the title product was obtained as a white powder. GC-MS (EI) m/z 239.2.

Intermediate 66 2-[(4,4-difluorocyclohexyl)carbonyl]hydrazine — tert-butyl carboxylate; O : joe

[00466] The title product was prepared from 4,4-difluorocyclohexane carboxylic acid (Combi-Blocks Inc.) according to the method described for Intermediate 54. MS (ESI) m/z 301.2 (M+ At)*.

Intermediate 67 4,4-Difluorocyclohexane carboxylic acid hydrazide

XIX

[00467] 3.39 g (12.2 mmol) of tert-butyl 2-[(4,4-difluorocyclohexyl)carbonyl]hydrazine carboxylate (Intermediate 66) was dissolved in 50 mL of ethyl acetate, then 50 mL of 2.5M solution of hydrogen chloride in ethyl acetate was added to the solution. The reaction mixture was stirred at room temperature for 16 hours and then concentrated. 15 ml of dichloromethane and 15 ml of distilled water were added to the residue, and the pH of the aqueous phase was basified with NaHCO solution; saturated, then the mixture was concentrated. The residue obtained was suspended in ethyl acetate, the insoluble solid was filtered off, the filtrate was dried over MgSO4 , filtered and concentrated. Thus, 2.08 g (93%)

158/323 of the title product was obtained as a white powder. MS (ESI) m/z 179.2 (M+H)*.

Intermediate 68 Ethyl 2-(2-nitrobenzyl)-1,3-dioxolan-2-yl acetate NO? COooEt

IF

[00468] 2.00 g (8.0 mmol) of ethyl 4-(2-nitrophenyl)-3-oxobutanoate (D. Royer et al., Tetrahedron 2008, 64:9607-9618) was dissolved in 25 mL of toluene, then 4.45 mL (79.6 mmol) of ethylene glycol and 0.23 g (1.19 mmol) of p-toluenesulfonic acid monohydrate were added to the resulting solution. Dean-Stark collector was applied to the flask and the reaction mixture was boiled for 6 hours and then stirred at 50°C for 48 hours. The resulting mixture was concentrated, the residue was taken up in water and extracted with diethyl ether. The organic phase was dried over MgSO4 , filtered and concentrated. The resulting crude product was purified by column chromatography using cyclohexane:ethyl acetate=4:1 as eluent. Thus, 0.68 g (29%) of the title product was obtained as a pale yellow oil. MS (ESID) m/z 296.2 (M+H)*.

Intermediate 69 Ethyl 2-(2-aminobenzyl)-1,3-dioxolan-2-yl acetate ef.

[00469] The title product was prepared from [2-(2-nitrobenzyl)-1,3-dioxolan-2-yl Ethyl jacetate (Intermediate 68) according to the method described for Intermediate 42. MS (ESI) m/z 266.2 (M+H)*.

Intermediate 70 1,5-Dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolane]-2(3H)-one or CO,

159 /323

[00470] The title product was prepared from ethyl [2-(2-aminobenzyl)-1,3-dioxolan-2-ylJacetate (Intermediate 69) according to the method described for Intermediate 43. MS (EST) m /z 220.2 (M+H)*.

Intermediate 71 Ethyl 3-amino-4(2-nitrophenyl)but-2-enoate

[00471] The title product was prepared from ethyl 4-(2-nitrophenyl)-3-oxobutanoate (D. Royer et al., Tetrahedron 2008, 64:9607-9618) according to the method described in step c ) of Method B) of Intermediate 1. MS (ESD m/z 252.1 (M+H)*.

Intermediate 72 Ethyl 3-amino-4-(2-nitropheny)butanoate Se

[00472] 1.29 g (6.1 mmol) of NaBH(OAc); was dissolved in 10 ml of acetic acid and a solution of 0.51 g (2.03 mmol) of ethyl 3-amino-4-(2-nitrophenyl)but-2-enoate (Intermediate 71) in 5 ml of acetic acid was slowly added dropwise to the above solution. The resulting mixture was stirred at room temperature for 48 hours. Then, the pH was adjusted to 8 with NaHCO solution; saturated and extracted with dichloromethane, then the organic phase was dried over MgSO, anhydrous, filtered and concentrated. Thus, 0.19 g (37%) of the title product was obtained as a yellow oil. MS (ESID) m/z 253.2 (M+H)*.

Intermediate 73 3-[tert-butoxycarbonyl)amino]-4-(2-nitrophenyl)butanoate — from ethyl Nut cooe

[00473] the

[00474] The title product was prepared from 3-amino-4-(2-

160 / 323 ethyl nitrophenyl)butanoate (Intermediate 72) according to the method described in step e) of Method B) of Intermediate 1. MS (ESI) m/z 375.1 (M+Na)*.

Intermediate 74 3-[tert-butoxycarbonyl)amino]|-4-(2-nitrophenyl)butanoic acid vo,

[00475] If"

[00476] The title product was prepared from ethyl 3-[tert-butoxycarbonyl)amino]-4-(2-nitrophenyl)butanoate (Intermediate 73) according to the method described in step f) of Method B) of Intermediate 1. MS (ESD m/z 347.1 (M+Na)*.

Intermediate 75 4-(2-aminophenyl)-3-[(tert-butoxycarbonyl)amino]butanoic acid-

[00477] The title product was prepared from 3-[tert-butoxycarbonyl)amino]-4-(2-nitrophenyl)butanoic acid (Intermediate 74) according to the method described in Method B) of Intermediate 2. MS ( ESI) m/z 295.1 (M+H)*.

Intermediate 76 (2-0Xx0-2,3,4,5-tetrahydro-1H-1-benzazepin-4-i) tert-butyl carbamate or

[00478] The title product was prepared from 4-(2-aminophenyl)-3-[(tert-butoxycarbonyl)amino]butanoic acid (Intermediate 75) according to the method described for Intermediate 3. MS (ESI) m /z 299.0 (M+Na)*.

161 /323 Intermediate 77 (tert-butyl 2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-iDcarbamate

[00479] The title product was prepared from fert-butyl (2-OxO-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate (Intermediate 76) according to the method described for Intermediate 4, which was used without further purification.

Intermediate 78 trans-4-(pyrrolidin-1-ylcarbonylcyclohexane carboxylic acid hydrazide CO quo a) methyl trans-4-pyrrolidin-1-ylcarbonyl]cyclohexane carboxylate

[00480] A mixture of 186 mg (1 mmol) trans-4-(methoxycarbonyl)cyclohexane carboxylic acid (Combi-Blocks Inc.), 83.5 uL (1 mmol) pyrrolidine, 5 mL dry DMF, 348 µl (2 mmol) of DIPEA, 230 mg (1.2 mmol) of EDC, and 162 mg (1.2 mmol) of HOBt was stirred at room temperature for 24 hours. Ethyl acetate and aqueous NaHCO solution; were added to the reaction mixture. The phases were separated and the aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed with 1N hydrochloric acid and water, dried over anhydrous Na 7 SO, filtered and concentrated. Thus, 180 mg (75%) of the title product was obtained. GC-MS (EI) m/z 239. b) trans-4-(pyrrolidin-1-ylcarbonyl)cyclohexane carboxylic acid hydrazide

[00481] 180 mg (0.75 mmol) of methyl trans-4-(pyrrolidin-1-ylcarbonyl)cyclohexane carboxylate, 1.1 ml of methanol and 1.1 ml of hydrazine-

162 /323 hydrate were stirred in a pressure resistant glass reactor at 75°C for 24 hours. The reaction mixture was concentrated and cyclohexane was added, then evaporated. Thus, 183 mg (76%) of the title product was obtained. GC-MS (EI) m/z 239.

Intermediate 79 trans-4-(morpholin-1I-ylcarbonyl)cyclohexane carboxylic acid hydrazide o w DO pj'. a) methyl trans-4-morpholin-4-ylcarbonyl]cyclohexane carboxylate

[00482] The title product was prepared from trans-4-(methoxycarbonyl)cyclohexane carboxylic acid (Combi-Blocks Inc.) and morpholine according to the method described in step a) of Intermediate 78. GC-MS ( EI) m/z 255. b) trans-4-(morpholin-1-ylcarbonyl)cyclohexanecarboxylic acid hydrazide

[00483] The title product was prepared from methyl trans-4-(morpholin-4-ylcarbonyl)cyclohexane carboxylate according to the method described in step b) of Intermediate 78. GC-MS (EI) m/ z 255.

Intermediate 80 trans-4-(dimethylamino)cyclohexane carboxylic acid hydrazide À > Oy

[00484] The title product was prepared from methyl trans-4-(dimethylamino)cyclohexane carboxylate (EP 1582 521 AI (05,10,2005) TANABE SEIYAKU CO.) according to the method described for Intermediate 65 MS (ESI) m/z 186.3 (M+H)*.

163 /323 Intermediate 81 frans-4-(morpholin-4-yl)cyclohexane carboxylic acid hydrazide

The "O.P.

[00485] The title product was prepared from methyl trans-4-(morpholin-4-yl)cyclohexane carboxylate (EP 1582 521 A1 (05,10,2005) TANABE SEIYAKU CO.) according to the method described for Intermediate 65. GC-MS (ED) m/z 227 Intermediate 82 1-(pyrimidin-2-i)azetidine-3-carboxylic acid hydrazide

the DN,

[00486] The title product was prepared from methyl 1-(pyrimidin-2-yl)azetidine-3-carboxylate (WO 2006/124748 A2 (2006-11-23) LEXICON GENETICS INCORP.) according to the method described for Intermediate 65. MS (ESID) m/z 194.2 (M+H)*. Intermediate 83 1-(Pyridin-2-iDazetidine-3-carboxylic acid hydrazide Cx Dt

[00487] The title product was prepared from methyl 1-(pyridin-2-iDazetidine-3-carboxylate (WO 2017/007756 Al (12.01.2017) RODIN THERAPEUTICS INC.) according to the method described for Intermediate 65. GC-MS (EI) m/z 192 Intermediate 84 Ethyl (trans)-3-methyl-2-0x0-1-0xa-3-azaspiro[4,5]decane-8-carboxylate

164 / 323 ds —N Ox and Intermediate 85 (cis)-3-methyl-2-0x0-1-0xa-3-azaspiro[4,5]decane-8-carboxylate

the gold

[00488] 1.8 g (45.0 mmol) of 60% sodium hydride dispersion in oil was suspended in 60 mL of dry DMF, cooled to 0-5°C, then 6.00 g (26.4 mmol) of a -1:1 mixture of ethyl (cis)-2-0x0-1-0xa-3-azaspiro[4.5]decane-8-carboxylate and (trans) 2-oxo-11-oxa-3 - ethyl azaspiro[4.5]decane-8-carboxylate (WO 2008/092887 Al, (07-08-2008) GLAXO GROUP LTD.) dissolved in 60 ml of DMF were added dropwise in such a way that the temperature of the mixture remained between 0 and 5°C. The reaction mixture was stirred for 20 minutes at this temperature, then 2.46 mL (39.5 mmol) of iodomethane was added dropwise over 20 minutes. The mixture was stirred for a further hour at 0-5°C, then allowed to warm to room temperature and stirred for 3 hours at this temperature. Then, 1.8 mL (31 mmol) of acetic acid was added dropwise over 10 minutes, after stirring for 15 minutes, the reaction mixture was concentrated and 90 mL of n-heptane was evaporated from the residue twice. 180 ml of ethyl acetate, 90 ml of NaHCO solution; saturated solution and 90 ml of water were added to the residue, the phases were separated, the organic phase was washed with 90 ml of NaCl, dried over Na 7 SO 3 , filtered and concentrated. The residue was purified by column chromatography using toluene:isopropanol=93:7 as eluent. The appropriate fractions were concentrated and the residues were crystallized from diisopropyl ether. Thus, 1.38 g (22%) of (trans)-3-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-

165 / 323 ethyl carboxylate (Intermediate 84) and 2.45 g (39%) of (cis)-3-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylate ethyl (Intermediate 85) were obtained as a white powder. GC-MS (EI) m/z 241. Intermediate 86 (trans)-3-methyl-2-0x0-1-0xa-3-azaspiro[4,5]decane-8-carboxylic acid hydrazide ds — OR the " sa

[00489] The title product was prepared from ethyl (trans)-3-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylate (Intermediate 84) according to the method described for Intermediate 65. GC-MS (EI) m/z 227. Intermediate 87 (cis)-3-methyl-2-oxo-1-oxa-3-azaspiro[4,5]decane-8-carboxylic acid hydrazide gives

[00490] The title product was prepared from ethyl (cis)-3-methyl-2-0xO-1-0xa-3-azaspiro[4.5]decane-8-carboxylate (Intermediate 85) according to method described for Intermediate 65. GC-MS (EI) m/z 227. Intermediate 88 5-[2-(5-fluoro-2-nitrophenyl)-1-hydroxyethylidene]-2,2-dimethyl-1,3-dioxane -4,6-dione or

IF the

AND

[00491] The title product was prepared from (5-fluoro-2-nitrophenyl)acetic acid (Combi-Blocks Inc.) according to the method described for Intermediate 39. MS (ESI) m/z 348.0 ( M+Na)*.

166 / 323 Intermediate 89 Methyl 4-(S-fluoro-2-nitroohenyl)-3-oxobutanoate

IF

[00492] The title product was prepared from 5-[2-(5-fluoro-2-nitrophenyl)-1-hydroxyethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione (Intermediate 88) according to the method described for Intermediate 40. MS (ESD m/2 273.1 (M+NH2)*. Intermediate 90 2-(5-fluoro-2-nitrobenzyl)-1,3-dioxolan-2 -yl Methyl Jacetate NO?COoMe

ONLY IT'S

[00493] The title product was prepared from methyl 4-(5-fluoro-2-nitrophenyl)-3-oxobutanoate (Intermediate 89) according to the method described for Intermediate 41. MS (ESI) m/z 317 .2 (M+NH2)*. Intermediate 91 Methyl 2-(2-amino-5-fluorobenzyl)-1,3-dioxolan-2-yl JAacetate NH2 COOoMe

ONLY

[00494] The title product was prepared from methyl [2-(5-fluoro-2-nitrobenzyl)-1,3-dioxolan-2-yl]acetate (Intermediate 90) according to the method described for Intermediate 42. MS (ESI) m/z 270.2 (M+H)*. Intermediate 92 T-Fluoro-1,5-dihydrospiro[1-benzazepine-4.2"-1,3]dioxolane]-2(3H)-one

167 /323 F of the

[00495] The title product was prepared from methyl [2-(2-amino-5-fluorobenzyl)-1,3-dioxolan-2-yl]acetate (Intermediate 91) according to the method described for Intermediate 43. MS (ESI) m/z 238.2 (M+H)*.

Intermediate 93 tert-Butyl (8-chloro-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-yl)carbamate

AND

[00496] 164 mg (0.48 mmol) of [7-chloro-2-(methylsulfanyl)-4,5-dihydro-3H-11-benzazepin-4-yl]fert-butyl carbamate (Intermediate 5) were dissolved in 3 ml of 1,4-dioxane and the resulting solution was heated to 90°C. 145 mg (241 mmol) of formyl hydrazide was added over 4 hours under argon. The reaction mixture was then stirred at 90°C for a further 8 hours and after cooling to room temperature, the solvent was evaporated in vacuo. The residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent. Thus, 145 mg (95%) of the title product was obtained as a white solid. MS (ESI) m/z 335.1 (M+H)*.

Intermediate 94 tert-Butyl (-bromo-8-chloro-5,6-dihydro-4H-[1,2,4]triazolo[4,3-all-benzazepin-5-i)carbamate Co

[00497] 528 mg (1.58 mmol) of (8-chloro-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1|benzazepin-5-yl]carbamate of tert-butyl (Intermediate 93) were dissolved in 35 mL of THF. 622 mg (3.5 mmol)

168 µl of N-bromosuccinimide was added and the resulting pale yellow solution was stirred at reflux for 60 minutes under illumination by a halogen lamp type RH-500 (Tracon Electric). At this time, the color of the solution initially darkened and then gradually became discolored. After cooling to room temperature, the solvent was evaporated in vacuo. The residue was purified by column chromatography using dichloromethane:methanol=97:3 as eluent. Thus, 592 mg (90%) of the title product was obtained as a white solid. MS (ESI) m/z 415.1 (M+H)*.

Intermediate 95 8'-Chloro-4'H,6'H-spiro[1,3-dioxolane-2,5*-[1,2,4]triazolo 4,3-a][1]benzazepine .v

It's Ls

[00498] 356.5 mg (1.405 mmol) of 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolane]-2(3H)-one — (Intermediate = 53) were dissolved in 22 ml of dichloromethane and 11 µl (0.144 mmol) of trifluoroacetic acid were added. Under argon, 249.4 mg (1.686 mmol) of trimethyloxonium tetrafluoroborate was added and the reaction mixture was stirred at room temperature for 24 hours. At this time, 422.0 mg (7.027 mmol) of formyl hydrazide was added in 5 portions at reflux temperature in 4 hours, then the reaction mixture was stirred at reflux temperature for 15 hours. The reaction mixture was concentrated and the residue was dissolved in 22 ml of dioxane and the mixture was stirred at 80°C for 2.5 hours. After cooling to room temperature, the solvent was evaporated in vacuo. The residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent. Thus, 248 mg (64%) of the title product was obtained. MS (ESI) m/z 335.1 (M+H)*.

Intermediate 96 1'-bromo-8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2.5º-

169 / 323 1,2,A]triazole) 4,3-a) 1]benzazepine to Ls

[00499] The title product was prepared from 8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3- a][1]benzazepine] (Intermediate 95) according to the method described for Intermediate 94. MS (ESI) m/z 358.0 (M+H)*.

Intermediate 97 frans-4-(piperidin-1-ylcarbonyl)cyclohexane carboxylic acid hydrazide-

OF NH

[00500] And a) methyl trans-4-(piperidin-I-ylcarbonyl]cyclohexane carboxylate

[00501] The title product was prepared from trans-4-(methoxycarbonyl)cyclohexane carboxylic acid (Combi-Blocks Inc.) and piperidine according to the method described in step a) of Intermediate 78. GC-MS ( EI) m/z 253. b) trans-4-(piperidin-1-ylcarbonyl)cyclohexane carboxylic acid hydrazide

[00502] The title product was prepared from methyl trans-4-(piperidin-1-ylcarbonyl)cyclohexane carboxylate according to the method described in step b) of Intermediate 78. GC-MS (EI) m/ z 253.

Intermediate 98 T-Chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxane]-2(3H)-one 4 o

No

a) [2-(5-Chloro-2-nitrobenzyl)-1,3-dioxan-2-yl Methyl jacetate EN =o C>

[00503] The title product was prepared from methyl 4-(5-chloro-2-nitrophenyl)-3-oxobutanoate (step b) of Method B) of Intermediate 1) and 1,3-propanediol according to the method described for Intermediate 41. MS (ESD m/z 330.2 (M+H)*. b) [2-2-amino-5-chlorobenzyl-1,3-dioxan-2-yl Methyl jacetate C>

[00504] The title product was prepared from methyl [2-(5-chloro-2-nitrobenzyl)-1,3-dioxan-2-yl]acetate (step a) of Intermediate 98) according to the method described for Intermediate 42. MS (ESI) m/z 322.2 (M+Na)*. c) 7T-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxane]-2(3H)-one

[00505] The title product was prepared from methyl [2-(2-amino-5-chlorobenzyl)-1,3-dioxan-2-yl]acetate (step b) of Intermediate 98) according to the method described for Intermediate 43. MS (ESI) m/z 268.1 (M+H)*.

Intermediate 99 (5s,8s)-1-OxO-2-(propan-2-yl)-2-azaspiro[4,5]methyl decane-8-carboxylate and Intermediate 100 (Sr, 8r)-1-OxO- Methyl 2-(propan-2-yl)-2-azaspiro[4,5-decane-8-carboxylate

171 /323 Ad AC Denon

[00506] A mixture of 0.9 g (4.0 mmol) of dimethyl trans-1-(2-oxoethyl)cyclohexane-1A-dicarboxylate (WO 2011/143150 AI, (05-10-2011) SANOFI), 40 mL of 1,2-dichloroethane, 316 uL (3.71 mmol) of isopropylamine and 637 uL (11.1 mmol) of acetic acid was cooled to 5°C and 2.36 g (11.1 mmol) of Sodium triacetoxyborohydride were added to the reaction mixture at such a rate to keep the internal temperature below 5°C. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h, then diluted with water. The pH of the mixture was adjusted to 8 by adding KCO solution; at 10%, the phases were separated and the water phase was extracted with dichloromethane. The combined organic phases were washed successively with 10% K,3CO; solution, water and brine, dried over Na7SO3, filtered and concentrated. The residue was dissolved in 40 ml of dry THF and 330 mg (2.94 mmol) of potassium tert-butoxide were added. The reaction mixture was stirred at room temperature for 3 h, then neutralized by adding CO; solid. After addition of water, the THF was evaporated and the water phase was extracted with ethyl acetate. The organic phase was dried over NaSO₄, filtered and concentrated. The residue was purified by flash column chromatography using cyclohexane : ethyl acetate = 45:55 mixture as eluent to give 56 mg (6%) of (5s,8s)-1-0xO-2-(propan-2- Methyl 11)-2-azaspiro[4,5]decane-8-carboxylate (Intermediate 99) as the first fraction and 172 mg (19%) of (5r,8r)-1-0x0-2-(propan-2- methyl yl)-2-azaspiro[4,5-decane-8-carboxylate (Intermediate 100) as the second fraction. GC-MS (EI) m/z 253.

Intermediate 101 (5s,8s)-1-OxO-2-(propan-2-yl)-2-azaspiro[4,5-decane-8-carbohydrazide dd

[00507] The title compound was prepared from methyl (55.85)-1-OxO-2-(propan-2-11)-2-azaspiro[4.5]decane-8-carboxylate (Intermediate 99) according to the method described for Intermediate 65. GC-MS (ED) m/z

253.

Intermediate 102 (Sr,8r)-1-0x0-2-(propan-2-yl)-2-azaspiro[4,5 decane-8-carmolianae

[00508] The title compound was prepared from methyl (5r,8r)-1-0xO-2-(propan-2-11)-2-azaspiro[4,5]decane-8-carboxylate (Intermediate 100) according to the method described for Intermediate 65. GC-MS (EI) m/z 253.

Intermediate 103 T-chloro-4-methoxy-1,3,4,5-tetrahydro-2H -1-benzazepine-2- —— Hs

N a) Methyl 4-(5-chloro-2-nitrophenyl-3-methoxybutanoate SO" &

[00509] A mixture of 1.37 g (5 mmol) of methyl 4-(5-chloro-2-nitrophenyl)-3-hydroxybutanoate (Intermediate 58), 90 mL of dichloromethane, 1.4 g of molecular sieves of 4ÁA, 3.21 g (15 mmol) of 1.8 bis(dimethylamino)naphthalene and 2.22 g (15 mmol) of trimethyloxonium tetrafluoroborate were stirred at room temperature for 20 h, then filtered and the solid material was washed with dichloromethane. The filtrate was washed with 3M HCl solution and water, dried over NaSO₄, filtered and concentrated. The residue was purified by flash column chromatography

173/323 using cyclohexane:ethyl acetate = 65:35 as eluent to give 1.097g (76%) of the title compound. MS (ESI) m/z 310.1 (M+Na)*. b) 4-5-chloro-2-nitrophenyl-3-methoxybutanoic acid

SO to

[00510] A mixture of 0.52 g (1.8 mmol) of methyl 4-(5-chloro-2-nitrophenyl)-3-methoxybutanoate (Step a) of Intermediate 103), 5 mL methanol, 0.9 mL of 4M NaOH and 1.6 mL of water was stirred at room temperature for 20 h, then the reaction mixture was acidified with IM HCl solution. The precipitated product was filtered, washed with water and dried to give 386 mg (78%) of the title compound. MS (EST) m/z 296.1 (M+Na)*. c) 4-2-amino-5-chlorophenyl)-3-methoxybutanoic acid O" to

[00511] The title compound was prepared from 4-(5-chloro-2-nitrophenyl)-3-methoxybutanoic acid (Step b) of Intermediate 103) according to the method described in Method B of Intermediate 2. MS ( ESI) m/z 244.1 (M+H)*. d) 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-11-benzazepin-2-one

No

[00512] The title compound was prepared from 4-(2-amino-5-chlorophenyl)-3-methoxybutanoic acid (Step c) of Intermediate 103) according to the method described for Intermediate 3. MS (ESI) m /z 226.1 (M+H)*. e) 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepine-2-thione

[00513] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) according to with the method described for Intermediate 23. MS (ESD) m/z 242.1

174/323 (M+H)*.

Intermediate 104 T-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-1,3]dioxepan]-2(3H)-one a)[2-5-chloro-2-nitrobenzyl)- 1,3-Dioxepan-2-yl Oil Methyl Jacetate

[00514] The title compound was prepared from methyl 4-(5-chloro-2-nitrophenyl)-3-oxobutanoate (Step b) of Method B of Intermediate 1) and 1,4-butanediol according to the method described for Intermediate 41. MS (ESD m/z 366.1 (M+Na)*. b) Methyl [2-2-amino-S-chlorobenzyl-1,3-dioxepan-2-yl]

CS

[00515] The title compound was prepared from methyl [2-(5-chloro-2-nitrobenzyl)-1,3-dioxepan-2-yl]acetate (Step a) of Intermediate 104) according to the method described for Intermediate 42 and was used without further purification in the next step. c) 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxepan]-2(3H)-one

[00516] The title compound was prepared from methyl [2-(2-amino-5-chlorobenzyl)-1,3-dioxepan-2-11]acetate (Step b) of Intermediate 104) according to the method described for Intermediate 43. MS (ESI) m/z 282.1 (M+H)*.

Intermediate 105 2-(methylsulfanyl)-4,5-dihydro-3H-1-benzazepin-4-

175 /323 tert-butyl ylcarbamate No A.

[00517] The title compound was prepared from tert-butyl (2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate (Intermediate 77) according to the method described for Intermediate 5 and was used without further purification in the next step. Intermediate 106 tert-Butyl T-fluoro-2-(methylsulfanyl)-4,5-dihydro-3H-1-benzazepin-4-ylcarbamate No a) 3-amino-4-5-fluoro-2-nitrophenyl) methyl but-2-enoate

NH IT'S

[00518] The title compound was prepared from methyl 4-(5-fluoro-2-nitrophenyl)-3-oxobutanoate (Intermediate 89) according to the method described in Step c) of Method B of Intermediate 1 and was used without further purification in the next step. b) methyl 3-amino-4-(5-fluoro-2-nitrophenyl)butanoate

NH IT'S

[00519] The title compound was prepared from methyl 3-amino-4-(5-fluoro-2-nitrophenyl)but-2-enoate (Step a) of Intermediate 106) according to the method described in Step d ) of Method B of Intermediate 1 and was used without further purification in the next step. c) methyl 3-[(tert-butoxycarbonyl)amino]-4-(5-fluoro-2-nitrophenyl)butanoate

176 /323 NHBoc CooMe Nut

IT'S

[00520] The title compound was prepared from methyl 3-amino-4-(5-fluoro-2-nitrophenyl)butanoate (Step b) of Intermediate 106) according to the method described in Step e) of Method B of Intermediate 1. MS (ESD m/z 379.1 (M+Na)*. d) Methyl 4-(2-amino-5-fluorophenyl)-3-[(tert-butoxycarbonyl]amino]butanoate NH2 NHBoc CooMe

IT'S

[00521] The title compound was prepared from methyl 3-[(tert-butoxycarbonyl)Jamino]-4-(5-fluoro-2-nitrophenyl)butanoate (Step c) of Intermediate 106) according to the method described for Intermediate 31 and was used without further purification in the next step. e) (7fluoro2-oxo2,34,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate — tert-butyl H o N.

LO NHBoc

[00522] The title compound was prepared from methyl 4-(2-amino-5-fluorophenyl)-3-[(tert-butoxycarbonyl)amino]butanoate (Step d) of Intermediate 106) according to the described method. for Intermediate 32. MS (ESD m/z 317.1 (M+Na)*.D (7-fluoro-2L-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4 -yl) tert-butyl carbamate H Ss N.

The NHBoc

[00523] The title compound was prepared from tert-butyl (7-fluoro-2-OxO-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl]carbamate (Step e)

177/323 of Intermediate 106) according to the method described for Intermediate 33 and was used without further purification in the next step. 2) tert-butyl [7-fluoro-2-(methylsulfanyl)-4,5-dihydro-3H-1-benzazepin-4-yl]carbamate

[00524] The title compound was prepared from tert-butyl (7-fluoro-2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate (Step £ ) of Intermediate 106) according to the method described for Intermediate 5 and was used without further purification in the next step.

Intermediate 107 methyl trans-4-[(4-methylpiperazin-1-yl)carbonyl cyclohexanecarbohydrazide a) trans-4-4-methylpiperazin-1-yl]carbonyl]cyclohexane carboxylate

[00525] The title compound was prepared from trans-4-(methoxycarbonyl)cyclohexane carboxylic acid and 11-methylpiperazine according to the method described in Step a) of Intermediate 78 and was used without further purification in the next step. b) trans-4-[(4-methylpiperazin-1-yl)carbonyl|cyclohexanecarbohydrazide

[00526] The title compound was prepared from methyl trans-4-[(4-methylpiperazin-1-yl)carbonyl|cyclohexanecarboxylate (Step a) of Intermediate 107) according to the method described in Step b) of Intermediate 78 and was used without further purification in the next step.

Intermediate 108 1(tetrahydro-2H-pyran-4-yl)piperidine-4-carbohydrazide

[00527] The title compound was prepared from 1-(tetrahydro-2H-

178 /323 ethyl pyran-4-yl)piperidine-4-carboxylate (WO 2016/138532 Al (01,09,2016) VERSION CORPORATION) according to the method described in Step b) of Intermediate 78 and was used without another purification in the next step.

Intermediate 109 Ethyl 1-(3S)-tetrahydrofuran-3-yl-ipiperidine-4-carbohydrazide a) 1-[(3S)-tetrahydrofuran-3-yl]piperidine-4-carboxylate OA Dcoca

[00528] A mixture of 1.93 g (7.97 mmol) of (3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (WO 2016/91776 Al (2016-06-16) EVOTEC AG), 2.46 mL (15.9 mmol) of ethyl piperidine-4-carboxylate, 39 mL of acetonitrile and 4.4 g (31.9 mmol) of K2CO; was stirred at 70°C for 24 h, then cooled to room temperature and diluted with ethyl acetate. The mixture thus obtained was washed with water and this water phase was discarded. The organic layer was washed with 1M HCl solution and this acidic water phase was basified with 10% K3 CO2 solution, extracted with ethyl acetate, the combined organic layers were dried over Na2 SO4 , filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane : methanol = 91:9 as eluent to give 603 mg (27%) of the title compound. GC-MS (ED) m/z 227. b) 1-[3S)-tetrahydrofuran-3-yl]-piperidine-4-carbohydrazide

[00529] The title compound was prepared from ethyl 1-[(3S)-tetrahydrofuran-3-yl]piperidine-4-carboxylate (Step a) of Intermediate 109) according to the method described in Step b) of Intermediate 78 and was used without further purification in the next step.

Intermediate 110 1-[GR )-tetrahydrofuran-S-yl piperidine-4-carbohydrazide

a) Ethyl 1-[(3R)-tetrahydrofuran-3-yl]piperidine-4-carboxylate

[00530] The title compound was prepared from (35)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (WO 2016/91776 Al (2016-06-16) EVOTEC AG) according to the method described in Step a) of Intermediate 109. GC-MS (EI) m/z 227. b) 1-[(3R)-tetrahydrofuran-3-yl Ipiperidine-4-carbohydrazide

[00531] The title compound was prepared from ethyl 1-[3R)-tetrahydrofuran-3-yl]piperidine-4-carboxylate (Step a) of Intermediate 110) according to the method described in Step b) of Intermediate 78 and was used without further purification in the next step.

Intermediate 111 ethyl cis-4-(4-methylpiperazin-1-yl)cyclohexanecarboxylate A IA Decos and Intermediate 112 trans-4-(4-methylpiperazin-1-yl)cyclohexanecarboxylate — from ethyl A IA Decos

[00532] A mixture of 1.27 mL (8 mmol) of ethyl 4-oxocyclohexanecarboxylate, 887 uL (8 mmol) of 1-methylpiperazine, 4 mL of methanol and 20 mL of dichloromethane was cooled to 5°C and 3, 39 g (16 mmol) of sodium triacetoxyborohydride was added to the reaction mixture at such a rate to maintain an internal temperature below 5°C. After the addition was complete, the reaction mixture was stirred at room temperature for 24 h, then concentrated. The residue was dissolved in IM HCl solution and extracted with dichloromethane. The acidic water phase was basified with 10% K2CO2 solution, extracted with ethyl acetate, the combined organic layers were dried over Na72SO4, filtered and concentrated to give

180/323 640 mg (30%) of the title compounds as a mixture. GC-MS (EI) m/z

254.

Intermediate 113 cis-4-(4-methylpiperazin-L-yl J-cyclohexanecarbohydrazide IA IA, and Intermediate 114 trans-4-(4-methylpiperazin-1-yl J-cyclohexanecarbohydrazide)

OO

[00533] The title compounds were prepared from a mixture of ethyl cis4-(4-methylpiperazin-1-yl)cyclohexanecarboxylate (Intermediate 111) and trans-4-(A-methylpiperazin-1-yl)cyclo- ethyl hexanecarboxylate (Intermediate 112) according to the method described in Step b) of Intermediate 78. GC-MS (EI) m/z 240.

Intermediate 115 Methyl 1-(pyridin-3-ylmethyl)pyrrolidine-3-carbohydrazide a) 1-(pyridin-3-ylmethyl)pyrrolidine-3-carboxylate

[00534] The title compound was prepared from methyl pyrrolidine-3-carboxylate and pyridine-3-carbaldehyde according to the method described for Intermediate 111 and 112 and was used without further purification in the next step. b) 1-(pyridin-3-ylmethyl)pyrrolidine-3-carbohydrazide

[00535] The title compound was prepared from methyl 1-(pyridin-3-ylmethyl)pyrrolidine-3-carboxylate (Step a) of Intermediate 115) according to the method described in Step b) of Intermediate 78. GC -MS (EI)

181 /323 m/z 220.

Intermediate 116 1-(pyridin-2-ylmethyl)pyrrolidine-3-carbohydrazide O o a) Methyl 1-(pyridin-2-ylmethyl)pyrrolidine-3-carboxylate

[00536] The title compound was prepared from pyrrolidine-3-carboxylate and methyl pyridine-2-carbaldehyde according to the method described for Intermediate 111 and 112. MS (ESD) m/z 221.2 (M+H )*. b) 1-(pyridin-2-ylmethyl)pyrrolidine-3-carbohydrazide

[00537] The title compound was prepared from methyl 1-(pyridin-2-ylmethyl)pyrrolidine-3-carboxylate (Step a) of Intermediate 116) according to the method described in Step b) of Intermediate 78 and was used without further purification in the next step.

Intermediate 117 Methyl 1-(pyridin-3-ylcarbonyl)-pyrrolidine-3-carbohydrazide is Nu a) 1-pyridin-3-ylcarbonyl)pyrrolidine-3-carboxylate

[00538] The title compound was prepared from pyridine-3-carboxylic acid and methyl pyrrolidine-3-carboxylate according to the method described in Step a) of Intermediate 78. MS (ESI) m/z 235.1 ( M+H)*. b) 1-(pyridin-3-ylcarbonyl)pyrrolidine-3-carbohydrazide

[00539] The title compound was prepared from methyl 1-(pyridin-3-ylcarbonyl)pyrrolidine-3-carboxylate (Step a) of Intermediate 117)

according to the method described in Step b) of Intermediate 78. GC-MS (ED m/z 234. Intermediate 118 1-(pyridin-2-ylcarbonyl)pyrrolidine-3-carbohydrazide a) 1-pyridin-2-ylcarbonyl J-pyrrolidine- Toove methyl 3-carboxylate

[00540] The title compound was prepared from pyridine-2-carboxylic acid and methyl pyrrolidine-3-carboxylate according to the method described in Step a) of Intermediate 78. MS (ESI) m/z 235.2 (M +H)*. b) 1-pyridin-2-ylcarbonyl pyrrolidine-3-carboxylic acid

[00541] The title compound was prepared from methyl 1-(pyridin-2-ylcarbonyl)pyrrolidine-3-carboxylate (Step a) of Intermediate 118) according to the method described for Intermediate 7. MS (ESI) m /z 221.1 (M+H)*. c) tert-butyl 2-([1-(pyridin-2-ylcarbonyl)pyrrolidin-3-11-carbonyl)hydrazinecarboxylate

[00542] The title compound was prepared from 1-(pyridin-2-ylcarbonyl)pyrrolidine-3-carboxylic acid (Step b) of Intermediate 118) according to the method described for Intermediate 54. MS (ESI) m/ z 335.2 (M+H)*. d) 1-(pyridin-2-ylcarbonyl)pyrrolidine-3-carbohydrazide

[00543] The title compound was prepared from 2-([1-(pyridin-2-

183 (Step c) of Intermediate 118) according to the method described for Intermediate 55 and was used without further purification in the next step.

Intermediate 119 4-methoxy-4-methylcyclohexanecarbohydrazide o a) ethyl 4-hydroxy-4-methylcyclohexanecarboxylate Or

[00544] Under argon to a stirred solution of 100 mL (220 mmol) of 2M trimethylaluminum in toluene, a solution of 8.7 mL (55 mmol) of ethyl 4-oxocyclohexanecarboxylate in 50 mL of toluene was added over 2 .5 h -60°C. After the addition was complete, the mixture was stirred at -60°C for 0.5 h, then allowed to warm to -20°C for 2 h. The reaction mixture was transferred for 25-30 min via a cannula to an ice-cold mixture of 180 mL of ethyl acetate, 425 mL of water, 75 mL of concentrated hydrochloric acid and 100 g of crushed ice, while maintaining an internal temperature below of 10ºC. The phases were separated, the organic phase was washed successively with 400 ml of water and 400 ml of brine, dried over NaSO₄, filtered and concentrated to give 5.44 g (53%) of the title compound. According to "NMR spectroscopy, it was a 28:72 mixture of cis- and trans-isomers. This mixture was used in the next step without further purification. b Ethyl A-methoxy-4-methylcyclohexanecarboxylate q

[00545] Under argon to a stirred mixture of 2.16 g (54 mmol) of 60% sodium hydride in mineral oil, 34 mL of dry THF, 200 mg (0.54 mmol) of tetrabutylammonium iodide, 49 mg (0.72 mmol) of imidazole and 3.36

184 / 323 mL (54 mmol) of iodomethane a solution of 3.36 g (18 mmol) of ethyl 4-hydroxy-4-methylcyclohexanecarboxylate (Step a) of Intermediate 119) in 21 mL of dry THF was added for 30-40 min at 20-25°C. The reaction mixture was stirred at room temperature for 3 h, then cooled to 0-5 °C and 2.28 mL (40 mmol) of acetic acid was added over 10 min. The mixture was stirred for 15 min, then poured into a mixture of 280 ml of diethyl ether and 120 ml of NaHCO solution; saturated. The phases were separated, the organic phase was washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography using n-hexane : ethyl acetate=85:15 as eluent to give 2.3 g (64%) of the title compound. According to 'HRMN spectroscopy, it was a 21:79 mixture of cis- and trans-isomers. c) 4-methoxy-4-methylcyclohexanecarbohydrazide

[00546] The title compound was prepared from ethyl 4-methoxy-4-methylcyclohexanecarboxylate (Step b) of Intermediate 119) according to the method described for Intermediate 65. According to NMR spectroscopy, it it was a 21:79 mixture of cis- and trans-isomers.

Intermediate 120 4-(2-Oxopyrrolidin-1-iDcyclohexanecarbohydrazide

N Y O. o

[00547] The title compound was prepared from ethyl 4-(2-oxopyrrolidin-1-yl)cyclohexanecarboxylate (WO2010/108052 A2 (20.03.2009) H. LUNDBECK A/S) according to the method described for Intermediate 65 and was used without further purification in the next step.

Intermediate 121 methyl trans-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylate

185 / 323 o.

F A oo and Intermediate 122 methyl cis-4-methoxy-4-(trifluoromethyl)cyclohexane carboxylate "e.g.

[00548] Under argon to a stirred mixture of 573 mg (2.7 mmol) of 4-hydroxy-4-(trifluoromethyl)cyclohexanecarboxylic acid, 5 ml of dry DMF and 5 ml of dry THF 324 mg (8.1 mmol) of 60% sodium hydride in mineral oil were added at 0°C. The reaction mixture was stirred at this temperature for 0.5 h, then 1.18 mL (18.9 mmol) of iodomethane was added and the reaction mixture was allowed to warm to room temperature. After 3 h of stirring at room temperature, 0.59 mL (9.45 mmol) of iodomethane was added and stirring was continued for 5 h. The reaction was quenched by adding 9 ml of IM hydrochloric acid solution, then diluted with dichloromethane and the phases were separated. The organic phase was washed with saturated NaHCO3 solution, dried over NaSO4 , filtered and concentrated. The residue was purified by column chromatography using cyclohexane:dichloromethane=1:1 as eluent to give 242 mg (37%) of trans-4-methoxy-4-(trifluoromethyl)cyclohexane-carboxylate — de — methyl ( Intermediate 121) as the first fraction and 277 mg (43%) of methyl cis-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylate (Intermediate 122) as the second fraction.

Intermediate 123 cis-4-methoxy-4-(trifluoromethyl)cyclohexanecarbohydrazide F. o

[00549] The title compound was prepared from cis-4-methoxy-4-

186 / 323 methyl (trifluoromethyl)cyclohexanecarboxylate (Intermediate 122) according to the method described for Intermediate 65. GC-MS (EI) m/z 240.

Intermediate 124 trans-4-methoxy-4-(trifluoromethyl)cyclohexanecarbohydrazide: F.o

[00550] The title compound was prepared from methyl trans-4-methoxy-4-(trifluoromethyl)cyclohexanecarboxylate (Intermediate 121) according to the method described for Intermediate 65. GC-MS (EI) m/z 240.

Intermediate 125 trans-4-[(4-methoxybenzyl)amino]cyclohexanecarbohydrazide

O “qo a) methyl trans-4-4-methoxybenzyl)aminocyclohexanecarboxylate Or

[00551] A mixture of 2.0 g (10.3 mmol) of methyl trans-4-aminocyclohexanecarboxylate hydrochloride (Combi-Blocks), 20 mL of 1,2-dichloroethane, 1.38 mL (11. 4 mmol) of 4-methoxybenzaldehyde and 1.12 mL (19.6 mmol) of acetic acid were cooled to 5°C and 6.78 g (32.0 mmol) of sodium triacetoxyborohydride were added to the reaction mixture at such a rate to keep the internal temperature below 5°C. After the addition was complete the reaction mixture was stirred at room temperature for 20 h, then diluted with water. The pH of the mixture was adjusted to 8 by adding 10% Na2 CO2 solution, the phases were separated and the water phase was extracted with dichloromethane. The combined organic phases were dried over MgSO4 , filtered and concentrated to give 1.48 g (52%) of compound

187 /323 holder. MS (ESD) m/z 278.2 (M+H)*. b) trans-4-[(4-methoxybenzyl)amino]cyclohexanecarbohydrazide

[00552] The title compound was prepared from methyl trans-4-[(4-methoxybenzyl)amino]cyclohexanecarboxylate (Step a) of Intermediate 125) according to the method described for Intermediate 65 and was used without further purification in the next step.

Intermediate 126 ans-4-ethoxyd-ethylcyclohexane-carbonhydrazide POA" a) Ethyl 4-ethyl-4-hydroxycyclohexanecarboxylate Der

[00553] The title compound was prepared from ethyl 4-oxocyclohexanecarboxylate and 25% solution of triethylaluminum in toluene according to the method described in Step a) of Intermediate 119. According to 'NMR spectroscopy, it it was a 27:73 mixture of cis- and trans-isomers. This mixture was used in the next step without further purification. b) ethyl trans-4-ethoxy-4-ethylcyclohexanecarboxylate

[00554] Under argon to a stirred mixture of 1.32 g (33 mmol) of 60% sodium hydride in mineral oil, 22 mL of dry toluene, 406 mg (1.1 mmol) of tetrabutylammonium iodide and 2, 85 mL (22 mmol) of ethyl trifluoromethanesulfonate, a solution of 2.2 g (11 mmol) of ethyl 4-ethyl-4-hydroxycyclohexanecarboxylate (Step a) of Intermediate 126) in 11 mL of dry toluene, was added for 30-40 min at 20-25°C. The reaction mixture was stirred at room temperature for 20 h, then cooled to 0-5°C and poured into an ice-cold mixture of 220 mL of ethyl acetate, 110 mL of NaHCO solution; saturated solution and 30 mL of water. THE

The mixture was stirred at 5°C for 0.5 h, then at room temperature for 20 h. The phases were separated, the organic phase was washed with brine, dried over Nas SO4 , filtered and concentrated. The residue was purified by column chromatography using n-hexane : ethyl acetate=94:6 as eluent to give 1.77 g (71%) of the title compound. According to 'NMR spectroscopy, it was a 3:97 mixture of cis- and trans-isomers. Cc) trans-4-ethoxy-4-ethylcyclohexane-carbohydrazide

[00555] The title compound was prepared from ethyl 4-ethoxy-4-ethylcyclohexanecarboxylate (Step b) of Intermediate 126) according to the method described for Intermediate 65. According to 'NMR spectroscopy, it was a 3:97 mixture of cis- and trans-isomers. This mixture was used in the next step without further purification.

Intermediate 127 4-Ethyl-4-methoxycyclohexane-carbohydrazide L NH=NHz

OA a) Á GRAGEa A Stdiialo ethanocatnontaio de ethyl

SHOVEL

[00556] The title compound was prepared from ethyl 4-ethyl-4-hydroxy-cyclohexanecarboxylate (Step a) of Intermediate 126) and methyl trifluoromethanesulfonate according to the method described in Step b) of Intermediate 126. According to 'HRMN spectroscopy, it was a 19:81 mixture of cis- and trans-isomers. b) 4-ethyl-4-methoxycyclohexane-carbohydrazide

[00557] The title compound was prepared from ethyl 4-methoxy-4-ethyl-cyclohexanecarboxylate (Step a) of Intermediate 127) according to the method described for Intermediate 65. According to 'NMR spectroscopy, it was a 20:80 mixture of cis- and trans-isomers. this mixture

189 / 323 was used in the next step without further purification.

Intermediate 128 ans telonitmelilicido-hexanecarbonhydrazide O, NANA? ethyl trans-4-ethoxy-4-methylcyclohexanecarboxylate

[00558] The title compound was prepared from ethyl 4-hydroxy-4-methylcyclohexanecarboxylate (Step a) of Intermediate 119) and ethyl trifluoromethanesulfonate according to the method described in Step b) of Intermediate 126. with 'NMR spectroscopy, it was a 4:96 mixture of cis- and trans-isomers. b) trans-4-ethoxy-4-methylcyclohexanecarbohydrazide

[00559] The title compound was prepared from ethyl 4-methoxy-4-ethyl-cyclohexanecarboxylate (Step a) of Intermediate 128) according to the method described for Intermediate 65. According to 'NMR spectroscopy, it was a 7:93 mixture of cis- and trans-isomers. This mixture was used in the next step without further purification.

Intermediate 129 4-Ethoxy-4-propylcyclohexanecarbohydrazide L NH-NH,

POR a) Ethyl 4-hydroxy-4-prop-2en-Lylcyclohexanecarboxylate

AD

[00560] To a solution of 11.9 mL (12.76 g, 75.0 mmol) of ethyl 4-oxocyclohexanecarboxylate in 225 mL of THF, 188 mL of 25% ammonium chloride solution and 9, 81 g (150 mmol) of zinc powder were added. The mixture was stirred at room temperature for 5 min, then 9.7 mL (13.56 g, 112.0 mmol) of allyl bromide was added.

190 /323 in drops for 20 min. At the end of the addition, the temperature of the reaction mixture rose to 42-43°C. The mixture was stirred at room temperature for 4 h, then poured into a mixture of 180 mL of water and 750 mL of ethyl acetate. After addition of 30 ml of 1.0 M hydrochloric acid solution, the phases were separated, the organic phase was washed with 2x375 ml of brine, dried over NaSO₄, filtered and concentrated to give 15.39 g (96%) of the title compound. According to 'NMR spectroscopy, it was a 60:40 mixture of cis- and trans-isomers. b Ethyl A-hydroxy-4-propylcyclohexanecarboxylate

PAD

[00561] A mixture of 14.86 g (70 mmol) of ethyl 4-hydroxy-4-(prop-2-en-1-yl)cyclohexanecarboxylate (Step a) of Intermediate 129), 250 mL of THF and 1.49 g 10% Pd on carbon was hydrogenated. Upon completion of the reaction, the mixture was filtered through Celite and washed with 3x25 mL of THF. The filtrate was concentrated and 3x100 mL of dichloromethane was evaporated from the residue to give 14.89 g (99%) of the title compound, which was used without further purification. c) Ethyl 4-ethoxy-4-propylcyclohexanecarboxylate

LO

[00562] The title compound was prepared from ethyl 4-hydroxy-4-propylcyclohexanecarboxylate (Step b) of Intermediate 129) and ethyl trifluoromethanesulfonate according to the method described in Step b) of Intermediate 126. with "NMR spectroscopy, it was a 16:84 mixture of cis- and trans-isomers. d) 4-ethoxy-4-propylcyclohexanecarbohydrazide

[00563] The title compound was prepared from ethyl 4-ethoxy-4-propylcyclohexanecarboxylate (Step c) of Intermediate 129) according to the method described for Intermediate 65. According to

191 /323 NMR spectroscopy, it was a 16:84 mixture of cis- and trans-isomers. This mixture was used in the next step without further purification.

Intermediate 130 4-methoxy-4-propylcyclohexanecarbohydrazide n NH-NH2

POR a) Ethyl 4-methoxy-4-propylcyclohexanecarboxylate

[00564] The title compound was prepared from ethyl 4-hydroxy-4-propylcyclohexanecarboxylate (Step b) of Intermediate 129) and methyl trifluoromethanesulfonate, according to the method described in Step b) of Intermediate 126. according to 'NMR spectroscopy it was a 57:43 mixture of cis- and trans-isomers. b) 4-methoxy-4-propylcyclohexanecarbohydrazide

[00565] The title compound was prepared from ethyl 4-methoxy-4-propylcyclohexanecarboxylate (Step a) of Intermediate 130) according to the method described for Intermediate 65. According to "NMR spectroscopy it was a 57:43 mixture of cis- and trans-isomers This mixture was used in the next step without further purification.

Intermediate 131 GR)-1-(pyridin-2-ylmethyl)pyrrolidine-3-carbohydrazide a) (3R)-1-(pyridin-2-ylmethyl)pyrrolidine-3-carboxylate methyl rooms

[00566] The title compound was prepared from methyl (3R)-pyrrolidine-3-carboxylate and pyridine-2-carbaldehyde according to the method described for Intermediate 111 and 112. MS (ESD) m/z 221.1 (M+H)*.

b) 3R)-1-(pyridin-2-ylmethyl)pyrrolidine-3-carbohydrazide

[00567] The title compound was prepared from methyl (3R)-1-(pyridin-2-ylmethyl)pyrrolidine-3-carboxylate (Step a) of Intermediate 131) according to the method described in Step b) of Intermediate 78 and was used without further purification in the next step. Intermediate 132 (3S)-1-(pyridin-2-ylmethyl-pyrrolidine-3-carbohydrazide

CO a) Methyl (35)-1-(pyridin-2-ylmethyl)pyrrolidine-3-carboxylate

[00568] The title compound was prepared from methyl (3S)-pyrrolidine-3-carboxylate and pyridine-2-carbaldehyde according to the method described for Intermediate 111 and 112. MS (ESD) m/z 221.1 (M+H)*. b) (3S5)-1-(pyridin-2-ylmethyl)pyrrolidine-3-carbohydrazide

[00569] The title compound was prepared from methyl (35)-1-(pyridin-2-ylmethyl)pyrrolidine-3-carboxylate (Step a) of Intermediate 132) according to the method described in Step b) of Intermediate 78 and was used without further purification in the next step. Intermediate 133 GR)-1-(pyridin-3-ylmethyl)pyrrolidine-3-carbohydrazide a) (3R)-1-(pyridin-2-3ylmethyl)pyrrolidine-3-carboxylate

[00570] The title compound was prepared from methyl (3R)-pyrrolidine-3-carboxylate and pyridine-3-carbaldehyde according to the method described for Intermediate 111 and 112. MS (ESD) m/z 221.1 (M+H)*.

b) 3R)-1-(pyridin-3-ylmethyl)pyrrolidine-3-carbohydrazide

[00571] The title compound was prepared from methyl (3R)-1-(pyridin-3-ylmethyl)pyrrolidine-3-carboxylate (Step a) of Intermediate 133) according to the method described in Step b) of Intermediate 78 and was used without further purification in the next step.

Intermediate 134 BS)-1-(pyridin-3-ylmethyl)pyrrolidine-3-carbohydrazide a) (35)-1-(pyridin-2-3ylmethyl)pyrrolidine-3-carboxylate methyl

[00572] The title compound was prepared from methyl (3S)-pyrrolidine-3-carboxylate and pyridine-3-carbaldehyde according to the method described for Intermediate 111 and 112. MS (ESD) m/z 221.1 (M+H)*. b) (3S5)-1-(pyridin-3-ylmethyl)pyrrolidine-3-carbohydrazide

[00573] The title compound was prepared from methyl (35)-1-(pyridin-3-ylmethyl)pyrrolidine-3-carboxylate (Step a) of Intermediate 134) according to the method described in Step b) of Intermediate 78 and was used without further purification in the next step.

Intermediate 135 trans-4-(pyridin-2-ylamino]cyclohexanecarbohydrazide 7 a) trans-4-IA Ne [methyl]cyclohexanecarboxylate”-

[00574] A mixture of 1.5 g (7.745 mmol) of methyl trans-4-aminocyclohexanecarboxylate hydrochloride, 4 ml (46.5 mmol) of 2-fluoropyridine and 1.35 ml (7.75 mmol) of DIPEA was stirred at 125 °C in a

194 / 323 pressure resistant glass reactor for 20 hours, then cooled to room temperature. The reaction mixture was diluted with 20 ml of ethyl acetate, washed with 2x30 ml of water and saturated NaCl solution, the organic phase was dried over anhydrous Na2SO, filtered and concentrated to give 325 mg (18%) of the title compound. MS (ESI) m/z 235.1 (M+H)*. b) trans-4-(pyridin-2-ylamino)cyclohexanecarbohydrazide

[00575] The title compound was prepared from methyl trans-4-(pyridin-2-ylamino)cyclohexanecarboxylate (Step a) of Intermediate 135) according to the method described in Step b) of Intermediate 78 and was used without further purification in the next step.

Example 1 8-Chloro-1-[1-(pyridin-2-yl)piperidin-4-yl]-5,6-dihydro-4H-1,2,A]triazolo[4,3-a][ 1]benzazepin-5-yl |ferc-butyl carbamate

Z 2 2X,

NL

[00576] A mixture of 236 mg (0.72 mmol) tert-butyl (7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate (Intermediate 4), mL of xylene and 190 mg (0.86 mmol) of 1-(pyridin-2-yl)piperidine-4-carbohydrazide (DM Beal et al., Tetrahedron Lett 2011, 52:5913-5917) was stirred under argon for 24 hours, then the reaction mixture was concentrated and the residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 200 mg (56%) of the title product was obtained. MS (ESI) m/z 495.3 (M+H)*.

Example 2 8-Chloro-1-[1-(pyridin-2-yl)piperidin-4-yl]-5,6-dihydro-4H-1,2,A4]triazolo[4,3-a][ 1]benzazepine-5-amine

195 / 323 or

[00577] To a solution of 200 mg (0.4 mmol) of [8-chloro-1-[1-(pyridin-2-yl)piperidin-4-yl]-5,6-dihydro-4H- [1,2,4]triazolo[4,3-a][1]benzazepin-5-yl]fert-butyl carbamate (Example 1) in 10 ml of ethyl acetate, 5 ml of 2.5M chloride solution of hydrogen in ethyl acetate were added and the reaction mixture was stirred at room temperature for 5 hours. Diethyl ether was added and the mixture was stirred at room temperature for 30 minutes. The precipitated product was filtered, washed with diethyl ether and dried. The product was dissolved in a mixture of dichloromethane and NaHCO; saturated solution, after one hour of stirring, the phases were separated and the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over NaSO, anhydrous, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=4:] as eluent. Thus, 96 mg (61%) of the title product was obtained. MS (EST) m/z 395.3 (M+H)*.

Example 3 N-[8-Chloro-[1-(pyridin-2-yl)piperidin-4-yl]-5,6-dihydro-4H-1,2A]triazolo[4,3-a][ 1]Benzazepin-5-yl Jacetamide S, A, nZ

THERE

[00578] A mixture of 43 mg (0.1 mmol) of 8-chloro-1-[1-(pyridin-2-yl)piperidin-4-11]-5,6-dihydro-4H-[1] ,2 A4]triazolo[4,3-a][1 Ibenzazepine-5-amine (Example 2), | mL of pyridine and 82 uL (0.9 mmol) of acetic anhydride was stirred at room temperature for 20 hours, then 5 mL of water

196 / 323 were added to the reaction mixture and extracted three times with 20 mL of dichloromethane. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. Thus, 23 mg (48%) of the title product was obtained. MS (ESID) m/z 437.2 (M+H)*.

Example 4 N-(8-Chloro-[1-(pyridin-2-yl)piperidin-4-yl]-5,6-dihydro-4H - 1,2A]triazolo[4,3-a][ 1]benzazepin-5-yl)-2-methylpropanamide

THE

NL CO £

[00579] To a mixture of 62 mg (0.157 mmol) of 8-chloro-1-[1-(pyridin-2-yl)piperidin-4-yl]-5,6-dihydro-4H-[1, 2,4]triazolo[4,3-a][1]/benzazepine-5-amine (Example 2), 10 mL of dichloromethane and 40 ul (0.23 mmol) of DIPEA, 24 ul (0.23 mmol) of isobutyryl chloride were added and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with dichloromethane, washed with water, the organic phase was dried over NaSO, anhydrous, filtered and concentrated. The residue was crystallized with hexane to give 60 mg (82%) of the title product. MS (ESI) m/z 465.2 (M+H)*.

Example 5 [8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo 4,3-a 1 tert-butyl ]benzazepine-5-ylcarbamate Ss Method A)

[00580] A mixture of 2.26 g (6.9 mmol) of (7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate of tert-butyl (Intermediate 4),

140 mL of xylene and 1.96 g (8.33 mmol) of trans-4-(pyridin-2-yloxy)cyclohexane-carboxylic acid hydrazide (WO 2010/060836 (03.06.2010) F. HOFFMANN-LA ROCHE AG.) was refluxed for 20 hours under argon, then concentrated and the residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 2.76 g (78%) of the title product was obtained. MS (ESI) m/z 510.2 (M+H)*.

Method B)

[00581] To a mixture of 3/75 g (11 mmol) of tert-butyl [7-chloro-2-(methylsulfanyl)-4,5-dihydro-3H-1-benzazepin-4-yl]carbamate (Intermediate 5), 110 mL of xylene and 2.87 g (12.2 mmol) of trans-4-(pyridin-2-yloxy)cyclohexane carboxylic acid hydrazide, 0.1 mL of concentrated hydrochloric acid was added. under argon and the reaction mixture was refluxed for 18 hours, then concentrated and the residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 3.42 g (61%) of the title product was obtained. MS (ESI) m/z 510.2 (M+H)*.

Example 6 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazole 4,3-0 1] benzazepine-5-amine Ss

[00582] To a mixture of 2.76 g (5.41 mmol) of (8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro- 4H-[1,24]triazolo[4,3-a][1]benzazepin-5-yl] tert-butyl carbamate (Example 5), 100 ml of ethyl acetate and 100 ml of ethanol, 50 ml of 2.5M solution of hydrogen chloride in ethyl acetate was added and the reaction mixture was stirred at room temperature for 5 hours. Diethyl ether was added and the mixture was stirred at room temperature for 30 minutes. The product

The precipitate was filtered, washed with diethyl ether and dried. The product was dissolved in a mixture of dichloromethane and NaHCO; saturated. After one hour of stirring, the phases were separated and the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 1.85 g (83%) of the title product was obtained. MS (ESI) m/z 410.2 (M+H)*.

Example 7 (5S)-8-chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo 4,3- a][1]benzazepine-5-amine Za"A and Example 8 (SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro -4H-[1,2,A4]triazolo[4,3-a][1]benzazepine-5-amine Ao: NO,

LO

[00583] The title products were prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A] triazolo[4,3-a][1]benzazepine-S-racemic amine (Example 6) by chiral preparative HPLC (CHIRALPAK IA with 20 µm preparative stationary phase, 2.5x20cm; F=15mL/min, eluent: n- hexane: EtOH=8:2 + 0.3% diethylamine; isocratic, t=25°C) to give the (58) enantiomer (T, 11.7 min; [5 = -21.1° (c=0.1; methanol ); Example 7) and the (SR) enantiomer (T, 14.9 min; [a = +14.5º (c=0.1; methanol); Example 8). The absolute configuration of the compounds was determined by the VCD method and by 'H NMR spectroscopy of the pairs.

199/323 diastereomers synthesized therefrom.

Example 9 N-(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2A]triazole 4,3-a] 1]benzazepin-5-yl)acetamide Ss

DAL

[00584] A mixture of 82 mg (0.2 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6), 2 mL of pyridine and 190 uL (2.0 mmol) of acetic anhydride was stirred at room temperature for 20 hours , then 5 ml of water was added to the reaction mixture and extracted three times with 20 ml of dichloromethane. The combined organic phases were dried over anhydrous NaSO, filtered and concentrated. Thus, 67 mg (74%) of the title product was obtained. MS (ESI) m/z 452.2 (M+H)*.

Example 10 N-f8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3- a][1]benzazepin-5-yl glycinamide AO.

It's CO, a) 2-((8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2A]triazolo[4 ,3-a][1]benzazepin-5-yl Yamino)-2-oxoethyl | tert-butyl carbamate

[00585] A mixture of 87 mg (0.21 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6), 3 mL DMF, 40 mg (0.23 mmol) Boc-glycine, 95 mg (0.25 mmol ) of HBTU and 44 uL (0.32 mmol) of TEA was stirred at room temperature for 20 hours, then the mixture of

200 / 323 reaction was concentrated and NaHCO solution; saturated was added to the residue. The precipitated product was filtered, washed with water, and dried. Thus, 91 mg (76%) of the title product was obtained. MS (ESI) m/z 567.3 (M+H)*. b) N-(8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo[4,3- a][1 ]|benzazepin-5-yl |glycinamide

[00586] To a mixture of 90 mg (0.16 mmol) of [2-((8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di- tert-butyl hydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepin-5-11βamino)-2-oxoethyl]carbamate (step a) of Example 10), 5 mL of ethyl acetate and 5 mL of ethanol, 2 mL of a 2.5M solution of hydrogen chloride in ethyl acetate were added and the reaction mixture was stirred at room temperature for 5 hours, then concentrated. The residue was dissolved in a mixture of dichloromethane and NaHCO3, saturated after one hour of stirring, the phases were separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over NaSO, anhydrous, filtered and concentrated. Thus, 49 mg (66%) of the title product was obtained. MS (ESI) m/z 467.2 (M+H)*.

Example 11 N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazole 4 ,3-a][1]benzazepin-5-ylglycinamide O,CO,a)[2-(1(55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl] -5,6-dihydro-4H-1,2A]triazolo[4,3-a][1]benzazepin-5-yl Yamino)-2-oxoethyl | tert -butyl carbamate

[00587] The title product was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepine-5-amine (Example 7) according to the method described in step a) of Example 10. MS (ESI) m/z 567.2 (M +H)*.

201 /323 b N-((5S)-8-chloro-1-[trans-4-(pyridin-2-1loxy)cyclohexyl]-5,6-dihydro-4H-1,2A]triazole [4,3-a][1 Ibenzazepin-5-yl |glycinamide

[00588] The title product was prepared from [2-(([(5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di- tert-butyl hydro-4H-[1,2A]triazolo[4,3-a][1]benzazepin-5-11]-2-oxoethyl |carbamate (step a) of Example 11) according to the method described in step b) of Example 10.

[0] 3º =-33.2º (c=0.1; methanol); MS (ESI) m/z 467.2 (M+H)*. Example 12 N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazole 4 ,3-a][1]benzazepin-5-ylglycinamide AO. x CO, a) [2-(1(5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl tert-butyl]-5,6-dihydro-4H-1,2A]triazolo[4,3-a][1|benzazepin-5-11]amino)-2-oxoethyl lcarbamate

[00589] The title product was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-al[1]benzazepine-5-amine (Example 8) according to the method described in step a) of Example 10. MS (ESI) m/z 567.2 (M+ H)*. b) NHI(SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl |-5,6-dihydro-4H-1,2A]triazolo[4,3 -a][1]benzazepin-5-yl)glycinamide

[00590] The title product was prepared from [2-([(5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro -4H-[1,2 A]triazolo[4,3-a][1]benzazepin-5-11 (Jamino)-2-oxoethyl] tert-butyl carbamate (step a) of Example 12) according to the described method in step b) of Example 10.

[0] 5° =+18.4° (c=0.1; methanol); MS (ESI) m/z 467.2 (M+H)*. Example 13 (25)-2-amino-N-[(5R)-8-chloro-1-[trans-4-(pyridin-2-

202 / 323 yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl)-2-phenylacetamide and AO a) [(15)-2-(1(5SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1 Ibenzazepin-5-ylamino)-2-oxo-1-phenylethyl | tert-butyl carbamate

[00591] The title product was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepine-5-amine (Example 8) and Boc-Phg-OH according to the method described in step a) of Example 10. MS (ESI) m/ z 643.2 (M+H)*. b) (25)-2-amino-N-[(5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- [1,2 A]triazolo[4,3-a][1 Ibenzazepin-5-yl1-2-phenylacetamide

[00592] The title product was prepared from [(15)-2-(((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6 tert-butyl -dihydro-4H-[1,24]triazolo[4,3-a][1]benzazepin-5-11Jamino)-2-oxo-1-phenylethyl carbamate (step a) of Example 13 ) according to the method described in step b) of Example 10. MS (ESI) m/z 543.2 (M+H)*.

Example 14 (2R)-2-amino-N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- [1,2,4]triazolo[4,3-a][1]benzazepin-5-yl)-2-phenylacetamide and AO a) [(1R)-2-(1(5SR)-8-chloro-1 -[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a][1]benzazepin-5-yl JYamino)-2-0x0-1-

203 / 323 phenylethyl | tert-butyl carbamate

[00593] The title product was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepine-5-amine (Example 8) and Boc-D-Phg-OH according to the method described in step a) of Example 10. MS (ESI) m/z 643.2 (M+H)*. b) (2R)-2-amino-N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- [1,2 A]triazolo[4,3-a][1 Ibenzazepin-5-yl 1-2-phenylacetamide

[00594] The title product was prepared from [(1R)-2-(((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6 tert-butyl -dihydro-4H-[1,24]triazolo[4,3-a][1]benzazepin-5-11Jamino)-2-oxo-1-phenylethyl carbamate (step a) of Example 14 ) according to the method described in step b) of Example 10. MS (ESI) m/z 543.2 (M+H)*.

Example 15 N-(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3] -a][1]benzazepin-5-yl)-2-hydroxyacetamide AO,

[00595] 0.10 g (024 mmol) of S8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4 ]triazolo[4,3-a][1]benzazepine-5-amine (Example 6) was dissolved in 5 mL of DMF, then 0.10 g (0.27 mmol) of HBTU, 0.17 mL (1. 22 mmol) of triethylamine and 0.02 g (0.27 mmol) of hydroxyacetic acid were added. The reaction mixture was stirred for 16 hours at room temperature. The solution was concentrated, 20 mL of NaHCO solution; saturated solution were added to the residue, extracted twice with 20 ml of dichloromethane, the combined organic phases were dried over MgSO4 , filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=9:]1 as eluent. The expected product was crystallized by titration with diethyl ether to give 0.07

204 / 323 8 (62%) of the title product. LC-MS (ESID) m/z 468.2 (M+H)*.

Example 16 3-[8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3 -a][1]benzazepin-5-yl)-1,1-dimethylurea AO.

two

THERE /

[00596] To a stirred solution of 37 mg (0.23 mmol) of 1,1-carbonyldiimidazole and 3 mL of dichloromethane, a solution of 94 mg (0.23 mmol) of 8-chloro-1-[trans -4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1]|benzazepine-S-amine (Example 6) in 3 ml of DMF and 80 µl of DIPEA was added dropwise and the reaction mixture was stirred at room temperature for 1 hour. Then, 1 mL of a 2M solution of dimethylamine in THF was added dropwise to the mixture and the mixture was stirred for a further 2 hours at room temperature, then concentrated. The residue was dissolved in 20 ml of ethyl acetate and washed with saturated NaCl solution. The organic phase was dried over anhydrous NaSO, filtered and concentrated. The residue was purified by column chromatography using ammonium hydroxide: 1,4-dioxane:ethanol=1:40:1 as eluent. Thus, 22 mg (20%) of the title product was obtained. MS (ESI) m/z 481.2 (M+H)*.

Example 17 N-(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3] -a][1]benzazepin-5-yl-Nº,N'-dimethylglycinamide.

TO, PAN No

[00597] The title product was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4] triazole[4,3-

205 / 323 a][1]benzazepine-5S-amine (Example 6) according to the method described in Example 16. LC-MS (ESI) m/z 495.2 (M+H)*.

Example 18 N-(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo 4,3-a ][1 ]benzazepin-5-yl Imethanesulfonamide 7 *

LI v

[00598] To a solution of 200 mg (0.49 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6), 10 mL of dichloromethane and 84 uL (0.6 mmol) of triethylamine, 46 uL (0.6 mmol) of methanesulfonyl chloride were added and the reaction mixture was stirred at room temperature overnight. Then, an additional 84 uL (0.6 mmol) of triethylamine and 46 uL (0.6 mmol) of methanesulfonyl chloride were added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane, washed with NaHCO solution; and saturated NaCl solution, the organic phase was dried over NaSO, anhydrous, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 93 mg (39%) of the title product was obtained. MS (ESI) m/z 488.2 (M+H)*.

Example 19 Nf(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3- a][1]benzazepin-5-yl-N-methylmethane sulfonamide and NO,

LO AND

[00599] To a solution of 50 mg (0.1 mmol) of N-(8-chloro-1-[trans-4-

206 / 323 (pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1]benzazepin-5-1l |] methanesulfonamide (Example 18) in 10 mL of DMF, mg (0.25 mmol) of sodium hydride (60% oil dispersion) were added and the reaction mixture was stirred at room temperature for 15 minutes. 15 µl (0.24 mmol) of iodomethane was then added and the reaction mixture was stirred at room temperature overnight. Then, an additional 10 mg of sodium hydride (60% oil dispersion) and 15 ul of iodomethane were added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous NaSO, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent. Thus, 33 mg (65%) of the title product was obtained. MS (EST) m/z 502.2 (M+H)*.

Example 20 No. -(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3] -a][1]benzazepin-5-yl --N N-dimethylsulfamide AO.» Co Lx /

[00600] To a solution of 82 mg (0.2 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2,A4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6), 5 mL of dichloromethane and 35 ul (0.25 mmol) of triethylamine, 25 ul (0.23 mmol) ) of NN-dimethylsulfamoyl chloride were added and the reaction mixture was stirred at room temperature for 20 hours. Then, an additional 35 µl of triethylamine and µl of N,N-dimethylsulfamoyl chloride were added, and the mixture was stirred at 40°C for 48 hours. The reaction mixture was diluted with dichloromethane, washed with NaHCO; saturated solution and saturated NaCl solution, the

The organic phase was dried over anhydrous Na2SO, filtered and concentrated. The residue "was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 38 mg (37%) of the title product was obtained. MS (ESD m/z 517.2 (M+H)*.

Example 21 8-Chloro-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo 4,3- a]|[1]benzazepine-5-amine Or,

LO a)(8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo[4,3-a ]|[ 1 Ibenzazepin-5-yl | tert-butyl methylcarbamate: ' A

[00601] To a solution of 98 mg (0.19 mmol) of (8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- [1,2,A4]triazolo[4,3-a][1]benzazepin-5-1l]fert-butyl carbamate (Example 5) in 10 mL of DMF, 20 mg (0.5 mmol) of sodium hydride Sodium (60% oil dispersion) was added and the reaction mixture was stirred at room temperature for 15 minutes, then 30 µl (0.48 mmol) of iodomethane was added and the mixture was stirred at room temperature overnight. Then, an additional 20 mg of sodium hydride (60% oil dispersion) and 30 µL of iodomethane were added to the reaction mixture and stirred at room temperature overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous NaSO, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 58 mg (58%) of the title product was obtained. MS (ESI) m/z 524.3

208 / 323 (M+H)*. b 8-chloro-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2A]triazolo[4,3-a ][1 ]benzazepine-5S-amine

[00602] The title product was prepared from (8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24 tert-butyl ]triazolo[4,3-a][1]benzazepin-5-11|]methylcarbamate (step a) of Example 21) according to the method described in Example 6. MS (ESI) m/z 424 .1 (M+H)*.

Example 22 8-Chloro-N,N-dimethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,24(triazolo[4.3 -a][1]benzazepine-5-amine

SS o

[00603] To a solution of 100 mg (0.24 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- [1,2,A]triazolo[4,3-a][1]benzazepine-S-amine (Example 6), 15 mL of methanol, 182 uL (2.44 mmol) of 37% formaldehyde and 28 uL (0.488 mmol) of acetic acid, 168 mg (0.79 mmol) of NaBH(OAc); were added under ice-cooling, and the reaction mixture was stirred at room temperature for 20 hours. Then 10 ml of NaHCO solution; saturated solution were added to the reaction mixture and concentrated. 30 ml of water was added to the residue and extracted with dichloromethane. The combined organic phases were dried over NaSO3, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 68 mg (64%) of the title product was obtained. MS (ESI) m/z 438.2 (M+H)*.

Example 23 8-Chloro-N-ethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di-

209 / 323 hydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine XX O... 7 x and NE a) (8-chloro-1-[trans- tert-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo[4,3-a][1 | butyl CX O. or ss

[00604] The title product was prepared from (8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1.2A ]triazolo[4,3-a][1]benzazepin-5-1] | tert-butyl carbamate (Example 5) and ethyl iodide, according to the method described in step a) of Example 21.b 8- chloro-N-ethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,24]triazolo[4,3-a][1 |benzazepine-5S-amine

[00605] The title product was prepared from (8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2, 4]triazolo[4,3-a][1]benzazepin-5-yl tert-butyl jetylcarbamate (step a) of Example 23) according to the method described in Example 6. MS (ESI) m/z 438, 2 (M+H)*. Example 24 8-Chloro-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2, 4]triazolo[4,3-a][1]benzazepine-5-amine

AAA

[00606] To a mixture of 0.5 g (1.22 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H -[1,2 A4]triazolo[4,3-a][1]benzazepine-5-amine (Example 6), 50 mL of 1,2-dichloroethane, 0.45 mL (6.13 mmol) of acetone and 134 µl (2.34 mmol) of acetic acid, 0.8 g (3.77 mmol) of NABH(OAc); was added in small portions under ice-water cooling, and the reaction mixture was stirred at room temperature for 20 hours. Then, 50 mL of water was added to the reaction mixture, the pH was adjusted to 12 with 5% NaOH solution and extracted with dichloromethane. The combined organic phases were dried over NaSO4 , filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent. Thus, 0.434 g (79%) of the title product was obtained. MS (ESI) m/z 452.2 (M+H)*.

Example 25 (5S)-8-chloro-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2,A4]triazolo[4,3-a][1]benzazepine-5-TS Co LA,

[00607] The title product was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepine-5-amine (Example 7) according to the method described in Example 24. et = -29.3° (c=0.1; methanol); MS (ESD) m/z 452.3 (M+H)*.

Example 26 (SR)-8-Chloro-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2,A]triazolo[4,3-a][1]benzazepine-5-amine o

[00608] The title product was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepine-5-amine (Example 8) according to the method described in

Example 24. | [ir = +30.7° (c=0.1; methanol); MS (ESI) m/z 452.3 (M+H)*. Example 27 8-Chloro-N-cyclobutyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1]benzazepine-5-amine

AT HERE

[00609] The title product was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4 ]triazolo[4,3-a][1]benzazepine-S-amine (Example 6) and cyclobutanol according to the method described in Example 24. MS (EST) m/z 464.2 (M+H)*. Example 28 8-Chloro-N-(oxetan-3-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl-5,6-dihydro-4H-1,2,A4] triazolo[4,3-a][1]benzazepine-5-amine

Hello

[00610] The title product was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4] triazolo[4,3-a][1]benzazepine-S-amine (Example 6) and oxetane-3-one according to the method described in Example 24. LC-MS (EST) m/z 466.2 (M +H)*. Example 29 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-N-(tetrahydro-2H-pyran-4-yl)-5,6-dihydro-4H-1 ,2 A]triazolo[4,3-a][1]benzazepine-5-amine cc o we

[00611] The title product was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24] triazole[4,3-

a][1]benzazepine-S-amine (Example 6) and tetrahydro-4H-pyran-4-one according to the method described in Example 24. MS (ESI) m/z 494.2 (M+H )*.

Example 30 8-Chloro-N-(4,4-difluorocyclohexyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1, 2,4]triazolo[4,3-a][1]benzazepine-5-amine

NA By

[00612] The title product was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4 ]triazolo[4,3-a][1/benzazepine-S-amine (Example 6) and 4,4-difluorocyclohexanone according to the method described in Example 24. MS (ESI) m/z 528.2 ( M+H)*.

Example 31 8-Methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3- hydrochloride a][1]benzazepine-5-amine a) (8-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 ,4 triazolo[4,3-a][1 ]|benzazepin-5-1l | tert-butyl carbamate

[00613] A mixture of 113 mg (0.35 mmol) of tert. butyl (Intermediate 15), 91 mg (0.39 mmol) of trans-4-(pyridin-2-yloxy)cyclohexane carboxylic acid hydrazide and 2 mL of 1,4-dioxane was stirred at 120°C for 2 hours under microwave irradiation (200W), then 80 mg (0.35 mmol) of silver benzoate was added and the reaction mixture was stirred under the same conditions for an additional 2 hours. The reaction mixture was filtered through Celite, washed with dichloromethane and concentrated. The residue "was purified by column chromatography using dichloromethane:methanol=96:4 as eluent. Thus, 103 mg (58%) of the title product was obtained. MS (ESI) m/z 506.3 (M+H)*. b) 8-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl|-5,6-dihydro-4H-[1,24]triazolo[4,3-a hydrochloride ][1 Ibenzazepine-5-amine

[00614] A mixture of 103 mg (0.2 mmol) of (8-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 4]triazolo[4,3-a][1]/benzazepin-5-yl]) tert-butyl carbamate (step a) of Example 31) and 3 mL of 2.5M solution of hydrogen chloride in ethyl acetate was stirred at room temperature for 2 hours. The precipitated crystals were filtered and washed with ethyl acetate. Thus, 65.4 mg (79%) of the title product was obtained. MS (EST) m/z 406.2 (M+H)*.

Example 32 S-Methoxy-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2, A4]triazolo[4,3-a][1]benzazepine-S-amine Meo ES

[00615] The title product was prepared from 8-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A]triazolo[4,3-a][1]benzazepine-5-amine (Example 31) according to the method described in Example 24. MS (ESI) m/z 448.3 (M+H)*.

Example 33 [1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3 -a][1]benzazepin-5-yl tert-butyl kcarbamate

214 /323 Page

[00616] 0.46 g (1.22 mmol) tert-butyl [2-(methylsulfanyl)-7-(trifluoromethyl)-4,5-dihydro-3H-1-benzazepin-4-yl]carbamate (Intermediate 50) was dissolved in 30 mL of xylene and 0.45 g (1.83 mmol) of trans-4-(pyridin-2-yloxy)cyclohexane carboxylic acid hydrazide was added to the solution. A drop of concentrated hydrochloric acid was added to the reaction mixture and the mixture was refluxed for 2 hours. After cooling to room temperature, the solution was concentrated. The residue was purified by flash chromatography using dichloromethane:methanol=95:5 as eluent. Fractions containing the expected product were concentrated and the product crystallized by titration with ether. Thus, 0.52 g (78%) of the title product was obtained. MS (ESI) m/z 544.2 (M+H)*.

Example 34 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,A4]triazolo[4, 3-a][1]benzazepine-5-amine

[00617] 0.52 g (0.95 mmol) of 1(1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H -[1,2,4]triazolo[4,3-a][1|benzazepin-5-yl]-fert-butyl]carbamate (Example 33) was dissolved in 30 ml of ethyl acetate and then 10 ml of 2 .5M solution of hydrogen chloride in ethyl acetate was added with cooling with ice water. The reaction mixture was stirred at room temperature for 4 hours, then mL of diethyl ether was added and the mixture was cooled again in a water bath. The precipitated product was filtered off, washed with

215 /323 diethyl ether and dried. Thus, 0.39 g (86%) of the title product was obtained. MS (EST) m/z 444.2 (M+H)*. The product was used in other reactions as a free base.

Example 35 N,N-Dimethyl-1-[frans-4-(pyridin-2-yloxy)cyclohexyl |-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,A] triazolo[4,3-a][1]benzazepine-5-amine

THE

[00618] The title product was prepared from 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2 ,A4]triazolo[4,3-a][1]benzazepine-5-amine (Example 34) according to the method described in Example 22. MS (ESD m/z 472.2 (M+H)*.

Example 36 N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1, 2,A4]triazolo[4,3-a][1]benzazepine-5-amine

FRAA

[00619] The title product was prepared from 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2 ,A4]triazolo[4,3-a][1]benzazepine-5-amine (Example 34) according to the method described in Example 24. MS (ESD) m/z 486.2 (M+H)*.

Example 37 8-Methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a] [1]benzazepine-5-amine

216 /323 oa) (8-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo[4,3 -a][1 Ibenzazepin-5-1l | tert-butyl carbamate

[00620] A mixture of 30.6 mg (0.1 mmol) of (7-methyl-2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl]carbamate of tert-butyl (Intermediate 23), 35.3 mg (0.15 mmol) of trans-4-(pyridin-2-yloxy)cyclohexane carboxylic acid hydrazide and 1 mL of n-butanol was refluxed for 48 hours, then concentrated The residue was used without further purification MS (ESI) m/z 490.3 (M+H)*.b 8-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl ]-5,6-dihydro-4H-[1,2,4-triazolo[4,3-a][1 Ibenzazepine-5-amine

[00621] A mixture of 91 mg (0.19 mmol) of (8-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2,A4]triazolo[4,3-a][1]benzazepin-5-yl]fert-butyl carbamate (step a) of Example 37) and 4.8 mL of 2.5M sodium chloride solution. hydrogen in ethyl acetate was stirred at room temperature for 2.5 hours. The precipitated crystals were filtered and washed with ethyl acetate. Ethyl acetate and aqueous K2CO solution; filtered hydrochloride salt was added and stirred for 10 minutes at room temperature. The phases were separated, the organic phase was dried over Na/-SO, anhydrous, filtered and concentrated. The residue was purified by gradient chromatography using dichloromethane:methanol=93:7—90:10 as eluent. Thus, 35 mg (49%) of the title product was obtained. MS (ESD m/z 390.2 (M+H)*. Example 38

217 /323 8S-Methyl-V-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl-S,6-dihydro-4H-1,2,A ]triazolo[4,3-a][1]benzazepine-5-amine

CC |

[00622] The title product was prepared from 8-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24] triazolo[4,3-a][1]benzazepine-5-amine (Example 37) according to the method described in Example 24. MS (ESI) m/z 432.3 (M+H)*.

Example 39 8-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a] [1]benzazepine-5-amine

[00623] A mixture of 0.68 g (1.8 mmol) of (1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro -4H-[1,2,A]triazolo[4,3-a][1]benzazepin-5-yl]fert-butyl carbamate (Example 33), 0.65 g (2.75 mmol) acid hydrazide trans-4-(pyridin-2-yloxy)cyclohexane carboxylic acid and 18 mL of n-butanol was refluxed for 29 hours, then concentrated. 25 mL of a 2.5M solution of hydrogen chloride in ethyl acetate was added to the residue and stirred at room temperature for 1.5 hours. The precipitated crystals were filtered and washed with ethyl acetate. Ethyl acetate aqueous KCO solution; were added to the filtered hydrochloride salt and stirred for 10 minutes at room temperature. The phases were separated, the organic phase was dried over anhydrous Na2SO4, filtered and concentrated.The residue was purified by gradient chromatography using dichloromethane:methanol 95:5—85:15 as the eluent. Thus, 0.64 g (78%) of the title product was obtained. MS (ESI) m/ z 454.1 (M+H)*.

Example 40 8-bromo-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl-5,6-dihydro-4H-1,2 ,A]triazolo[4,3-a][1]benzazepine-5-amine nl LA.

[00624] The title product was prepared from 8-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A] triazolo[4,3-a][1]benzazepine-5S-amine (Example 39) according to the method described in Example 24. MS (ESI) m/z 498.1 (M+H)*.

Example 41 8-Chloro-1-(3,3-difluorocyclobutyl)-V-(propan-2-yl)-5,6-dihydro-4H-[1,2,4-triazole 4,3-a][ 1]benzazepine-5S-amine Po,

LA a) [8-Chloro-1-(3,3-difluorocyclobutyl)-5,6-dihydro-4H-[1,2A4]triazolo[4,3-a][1-benzazepin-5-yl carbamate of rerc-butyl “o,

[00625] 0.19 g (0.59 mmol) of tert-butyl (7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate (Intermediate 4) was dissolved in 10 ml of xylene and 0.14 g (0.900 mmol) of 3,3-difluorocyclobutane carboxylic acid hydrazide (Intermediate 57) was added to the solution. The reaction mixture was refluxed under argon for 6 days and then concentrated. The product was purified by column chromatography using dichloromethane:methanol:25% ammonia solution =18:1:0.1 as eluent. The appropriate fractions were concentrated and the residue was crystallized by

219 /323 titration with ether. Thus, 0.11 g (42%) of the title product was obtained. MS (ESD m/z 425.2 (M+H)*. b) 8-Chloro-1-(3,3-difluorocyclobutyl)-5,6-dihydro-4H-[1,2,4]triazole [4,3-a][1 benzazepine-5-amine “Ao,

[00626] 0.10 g (0.25 mmol) of [8-chloro-1-(3,3-difluorocyclobutyl)-5,6-dihydro-4H-[1,2,A]triazolo[4, tert-Butyl 3-a][1]benzazepin-5-yl]carbamate (step a) of Example 41) was dissolved in 10 mL of ethyl acetate, then 2 mL of 2.5M solution of hydrogen chloride in acetate of ethyl was added to the solution. The reaction mixture was stirred at room temperature for 5 hours, then diethyl ether was added and the product was extracted twice with 20 mL of water. The pH of the combined aqueous phases was basified with NaCO solution; saturated and the highly precipitated mixture was extracted twice with 20 ml of dichloromethane. The combined organic phases were dried over MgSO4 , filtered and concentrated. Thus, 0.05 g (66%) of the title product was obtained. MS (ESD) m/z 325.2 (M+H)*. c) B8-chloro-1-(3,3-difluorocyclobutyl)-N-(propan-2-yl)-5,6-dihydro-4H-[1,2,4-triazolo[4,3-a] [1]benzazepine-5S-amine

[00627] The title product was prepared from 8-chloro-1-(3,3-difluorocyclobutyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a] [1]benzazepine-5-amine (step b) of Example 41) according to the method described in Example 24. MS (ESI) m/z 367.2 (M+H)*.

Example 42 8-Chloro-1-(4,4-difluorocyclohexyl)-N-(propan-2-yl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3 -a][1]benzazepine-5-amine

220 / 323

HERE

AAA a) tert. butyl

THE

[00628] The title product was prepared from tert-butyl (7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl]carbamate (Intermediate 4 ) and 4,4-difluorocyclohexane carboxylic acid hydrazide (Intermediate 67) according to the method described in step a) of Example

41. MS (ESD m/2 453.2 (M+H)*. b 8-Chloro-1-(4,4-difluorocyclohexyl)-5,6-dihydro-4H-[1.2 A ]triazolo[4,3-all1 benzazepine-5-amine “Oo,

[00629] The title product was prepared from [8-chloro-1-(4,4-difluorocyclohexyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3 -a][1]| tert-butyl benzazepin-5-ylcarbamate (step a) of Example 42) according to the method described in step b) of Example 41. MS (ESI) m/z 353.1 (M +H)*. c) 8-Chloro-1-(4,4-difluorocyclohexyl)-N-(propan-2-yl)-5,6-dihydro-4H-1,2 Altriazolo[4,3-a][ 1]benzazepine-5S-amine

[00630] The title product was prepared from 8-chloro-1-(4,4-difluorocyclohexyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3- a][1]|benzazepine-5-amine (step b) of Example 42) according to the method described in Example 24. MS (ESI) m/z 395.1 (M+H)*.

Example 43

221 /323 8-Chloro-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1] benzazepine-5-amine oa) ([8-chloro-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo[4,3- a]l[1 Ibenzazepin-5-yl | tert-butyl carbamate

AND

[00631] The title product was prepared from tert-butyl [7-chloro-2-(methylsulfanyl)-4,5-dihydro-3H-1-benzazepin-4-yl]carbamate (Intermediate 5) and trans-4-(trifluoromethyl)cyclohexane carboxylic acid hydrazide (Intermediate 55) according to the method described in Method B) of Example 5. MS (ESI) m/z 485.2 (M+H)*. b 8-chloro-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo[4,3-a][1|benzazepine-5 -the mine

[00632] The title product was prepared from (8-chloro-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4 ,3-a][1]benzazepin-5-yl] tert-butyl carbamate (step a) of Example 43) according to the method described in Example 6. MS (ESI) m/z 385.2 (M+ H)*.

Example 44 8-Chloro-N-(propan-2-yl)-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1]benzazepine-5-amine

[00633] The title product was prepared from 8-chloro-1-[trans-4-

222/323 (trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a][1]benzazepine-5-amine (Example 43) according to the method described in Example 24. MS (ESD m/z 427.2 (M+H)*.

Example 45 8-bromo-11-[trans-4-(trifluoromethylcyclohexyl]-5,6-dihydro-4H-1,2,4-triazolo 4,3-a][1]benzazepine-5-amine

[00634] The title product was prepared from tert-butyl (7-bromo-2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate (Intermediate 33 ) and trans-4-(trifluoromethyl)cyclohexane carboxylic acid hydrazide (Intermediate 55) according to the method described in Example

39. MS (ESD) m/z 431.1 (M+H)*.

Example 46 8-bromo-N-(propan-2-yl)-1-[trans-4-(trifuoromethyl)cyclohexyl-5,6-dihydro-4H-1,2,A4]triazolo[4 ,3-a][1]benzazepine-5-amine Op, E,

[00635] The title product was prepared from 8-bromo-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4 ,3-a][1]benzazepine-5S-amine (Example 45) according to the method described in Example 24. MS (ESID) m/z 471.1 (M+H)*.

Example 47 1st -[trans -4-(pyridin-2-yloxy)cyclohexyl]-8'-(trifluoromethyl)-4H,6th H-spiro[1,3-dioxolane-2,5*-[1, 2,4]triazolo[4,3-a][1]benzazepine

223 / 323

AOL

[00636] 0.80 g (2.79 mmol) of 7-(trifluoromethyl)-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolane]-2(3H)- One (Intermediate 43) was dissolved in 60 mL of dichloromethane, then 0.02 mL (0.28 mmol) of trifluoroacetic acid and 0.50 g (3.34 mmol) of trimethyloxonium tetrafluoroborate were added to the solution under argon. The reaction mixture was stirred at room temperature for 24 hours and then 0.80 g (3.34 mmol) of trans-4-(pyridin-2-yloxy)cyclohexane carboxylic acid hydrazide was added to the solution. The reaction mixture was refluxed for 6 hours, then the solution was concentrated. The residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent. The product-containing fractions were concentrated to give 0.53 g (39%) of the title product. MS (ESD m/z 487.2 (M+H)*. Example 48 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-4H-[1.2, A]triazolo[4,3-a][1]benzazepin-5(6H)-one

[00637] 0.54 g (1.11 mmol) of 1º-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8º -(trifluoromethyl)-4'H,6'H-spiro[1 ,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine] (Example 47) was dissolved in 20 ml of methanol and 25 ml of concentrated hydrochloric acid was added the solution. The reaction mixture was refluxed for 2 hours and then, after cooling to room temperature, 50 mL of water was added and the pH adjusted to 7-8 with 30% NaOH solution. The solution was extracted three times with 30 ml of ethyl acetate, and the combined organic phases were washed with water,

224 / 323 then with saturated NaCl solution, dried over MgSO₄, filtered and concentrated. The residue was purified by column chromatography using ethyl acetate:ethanol=3:1 as eluent. The appropriate fractions were concentrated and the residue was crystallized by titration with ether. Thus, 0.30 g (61%) of the title product was obtained. MS (ESI) m/z 443.2 (M+H)*.

Example 49 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3- a][1]benzazepin-5-ol

[00638] 0.32 g (0.72 mmol) of 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-4H-[1,2,4]triazolo[ 4,3-a][1]benzazepine-5(6H)-one (Example 48) was dissolved in 20 mL of methanol and the solution was cooled to 00°C. Under stirring and cooling with ice water, 0.03 g (0.87 mmol) of NaBH was added to the reaction mixture. The solution was stirred at 0°C for 10 min and then at room temperature for a further 2 hours. The reaction mixture was concentrated, 10 ml of water was added to the residue and the pH of the solution was adjusted to about 7 with 5% hydrochloric acid solution. The aqueous phase was extracted twice with 20 ml of dichloromethane, the combined organic phases were dried over MgSO4 , filtered and concentrated. The residue was crystallized by titration with ether. Thus, 0.32 g (99%) of the title product was obtained. MS (ESI) m/z 445.2 (M+H)*.

Example 50 S-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl |-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,A4]triazolo[ 4,3-a][1]benzazepine

225 / 323

[00639] 0.10 g (0.23 mmol) of 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[ 1,2 4]triazolo[4,3-a][1]benzazepin-5-ol (Example 49) was dissolved in 10 mL of DMF and the solution was cooled to 0°C. 8.1 mg (0.34 mmol) of sodium hydride (60% oil dispersion) was added to the solution and the mixture was stirred at 0°C for 1 hour. 28.0 µL (0.45 mmol) of iodomethane was added to the reaction mixture and allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was poured into water and extracted twice with 20 ml of ethyl acetate. The combined organic phases were washed with water and saturated NaCl solution, dried over anhydrous MgSO4 , filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=95:5" as eluent. The expected product was crystallized by titration with n-hexane to give 0.05 g (47%) of the title product. MS (ESI) m /z 459.2 (M+H)* Example 51 5-(cyclopropylmethoxy)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-di -hydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepine and no

[00640] 0.10 g (0.23 mmol) of 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[ 1,2 4]triazolo[4,3-a][1]benzazepin-5-ol (Example 49) was dissolved in 10 mL of DMF and the solution was cooled to 0°C. 8.1 mg (0.34 mmol) of sodium hydride (60% oil dispersion) was added to the solution and the mixture was stirred at 0°C for 1 hour. 87.3

226 / 323 uL (0.90 mmol) of (bromomethyl)cyclopropane was added to the reaction mixture and then allowed to warm to room temperature and stirred for 16 hours. Then, the solution was cooled again and another 4.0 mg (0.17 mmol) of sodium hydride (60% oil dispersion) and 43.7 uL (0.45 mmol) of (bromomethyl)cyclopropane were added to the mixture. reaction mixture. After stirring at room temperature for 6 hours, the reaction mixture was poured into water and extracted twice with 20 ml of dichloromethane. The combined organic phases were washed with water, dried over anhydrous MgSO, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=95:5 as eluent. The appropriate fractions were concentrated and the residue was crystallized by titration with n-hexane to give 0.07 g (65%) of the title product. MS (ESID) m/z 499.3 (M+H)*.

Example 52 5-f[tert-butyl(dimethylsilylJoxy)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl-5,6-dihydro-4H-1,2, A]triazolo[4,3-a][1]benzazepine co

SAY

[00641] 0.36 g (1.06 mmol) of 4-([tert-butyl(dimethyl)silylJoxy)-7-chloro-1,3,4,5-tetrahydro-2H-1-benzazepine- 2-thione (Intermediate 63) was dissolved in 20 mL of xylene and 0.42 g (1.80 mmol) of trans-4-(pyridin-2-yloxy)cyclohexane carboxylic acid hydrazide was added to the solution. The reaction mixture was refluxed for 96 hours, cooled to room temperature and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=95:5° as eluent. The appropriate fractions were concentrated and the residue was crystallized by titration with ether. Thus, 0.21 g (37%) of the title product was obtained. MS (ESI) m/z 525.2 (M+H)*.

227 /323 Example 53 8º -chloro-L1 -[trans -4-(pyridin-2-yloxy)cyclohexyl-4'H,6'H-spiro[1,3-dioxolane-2,5º-[1, 2,A4]triazolo[4,3-a][1]benzazepine CO Au, er 7 O

[00642] The title product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolane]-2(3H)-one (Intermediate 53) according to the method described in Example 47. MS (ESI) m/z 453.2 (M+H)*.

Example 54 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4H - 1,2A]triazolo 4,3-a) 1]benzazepin-5(621)-one

[00643] The title product was prepared from 8º -chloro-1*-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane -2.5"- [1,24]triazolo[4,3-a][1Ibenzazepine] (Example 53) according to the method described in Example 48. MS (EST) m/z 409.2 (M +H)*.

Example 55 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a] [1]benzazepin-5-ol A Qu, Method A)

[00644] 0.28 g (0.53 mmol) of 5-([tert-butyl(dimethyl)silyl]oxy)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]- 5,6-dihydro-4H-[1,2A]triazolo[4,3-

228 / 323 a][1]benzazepine (Example 52) was dissolved in 20 ml of THF. 1.07 mL (1.07 mmol) of 1M solution of tetrabutylammonium fluoride (TBAF) in THF was added dropwise to the above solution and the reaction mixture was stirred at room temperature for 5 hours. 50 ml of water was added to the reaction mixture and extracted twice with 50 ml of ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried over Na₂SO₄, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=90:10 as eluent. The appropriate fractions were concentrated and the residue was crystallized by titration with ether. Thus, 0.19 g (86%) of the title product was obtained. MS (ESD m/z 411.1 (M+H)*.

Method B)

[00645] The title product was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4H-[1,2A]triazolo[4,3-a] [1]benzazepine-S(6H)-one (Example 54) according to the method described in Example 49. MS (ESD m/z 411.2 (M+H)*.

Example 56 (SS)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo 4,3- a ][1]benzazepin-5-ol Cr Du, cc and Example 57 (SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di- hydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-ol CO Ox

[00646] The title products were prepared from 8-chloro-1-

229 / 323 [trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a][1]benzazepin-5 -ol racemic (Example 55) by chiral preparative HPLC (CHIRALPAK IA with 20 µm preparative stationary phase, 2.5x20cm; F=15mL/min, eluent: tert-butyl methyl ether:dichloromethane:ethanol=85:10:5 ; isocratic, t=25°C) to give the (55) enantiomer (T, 16.2 min; “&º[5; = -15.6º (c=0.1; chloroform); Example 56) and the (5R) enantiomer ) (T, 19.8 min; | Jaz = +11.6° (c=0.1; chloroform); Example 57). The absolute configuration of the compounds was determined by the VCD method and by 1 H NMR spectroscopy of the diastereomeric pairs synthesized therefrom.

Example 58 8-Chloro-S-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo 4,3- a][1]benzazepine

[00647] The title product was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24] triazolo[4,3-a][1]benzazepin-5-ol (Example 55) according to the method described in Example 50. MS (ESI) m/z 425.2 (M+H)*.

Example 59 5-(Cyclopropylmethoxy)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[ 4,3-a][1]benzazepine

the female

[00648] The title product was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4] triazolo[4,3-a][1]benzazepin-5-ol (Example 55) according to the method described in Example 51. MS (ESD m/z 465.2 (M+H)*.

Example 60 2-(18-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[ 4,3-a][1]benzazepin-5-yl-Yoxy)-N,N-ENA or AQ,

THE THERE Y

[00649] 0.08 g (019 mmol) of S8-chloro-1-[trans4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A] triazolo[4,3-a][1]Ibenzazepin-5-ol (Example 55) was dissolved in 8 mL of DMF, the solution was cooled to 0 °C and 0.05 g (1.32 mmol) of sodium hydride ( 60% oil dispersion was added and the resulting mixture was stirred at 0°C for half an hour. Then, 0.08 g (0.56 mmol) of 2-chloro-N,N-dimethylethanamine hydrochloride was added to the reaction mixture and stirred at room temperature for 16 hours. The reaction mixture was poured onto ice and extracted twice with mL of ethyl acetate. The combined organic phases were washed with water and saturated NaCl solution, dried over anhydrous MgSO₄, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol:25% ammonia =18:1:0.1 solution as eluent. The appropriate fractions were concentrated and the residue was crystallized by titration with diethyl ether to give 0.04 g (47%) of the title product. MS (ESID) m/z 482.2 (M+H)*.

Example 61 8º -Chloro-1"-[trans-4-(trifluoromethyl)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5*-[1,2,4] triazolo[4,3-a][1]benzazepine

THE

231 / 323

[00650] The title product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolane]-2(3H)-one (Intermediate 53) and trans-4-(trifluoromethyl)cyclohexane-carboxylic acid hydrazide (Intermediate 55) according to the method described in Example 47. MS (ESD) m/z 428.1 (M+H)*.

Example 62 8º-bromo-1"-[frans-4-(pyridin-2-yloxy)cyclohexyl-4' H,6º H-spiro[1,3-dioxolane-2,5º-[1,2,4 ]triazolo[4,3-a][1]benzazepine

CX

[00651] To a solution of 121 mg (0.41 mmol) of 7-bromo-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolane]-2(3H)- One (Intermediate 36) and 8 mL of dry dichloromethane, 3.11 uL (0.04 mmol) of trifluoroacetic acid and 72 mg (049 mmol) of trimethyloxonium tetrafluoroborate were added under a nitrogen atmosphere at room temperature. The reaction mixture was stirred at room temperature for 17 hours, then 107 mg (0.45 mmol) of trans-4-(pyridin-2-yloxy)cyclohexane carboxylic acid hydrazide was added and refluxed for 6.5 hours. . The reaction mixture was concentrated, 10 ml of toluene and 1 drop of acetic acid were added to the residue and refluxed for 3 hours, then the reaction mixture was concentrated. The residue was purified by gradient chromatography using dichloromethane:methanol=97:3—90:10 as eluent. Thus, 121 mg (60%) of the title product was obtained. MS (ESI) m/z 499.1 (M+H)*.

Example 63 1º-[trans-4-(pyridin-2-yloxy)cyclohexyl]|-4º H,6º H-spiro[1,3-dioxolane-2,5*-[1,2,4]triazolo[ 4,3-a][1]benzazepine

232 /323 with

THE

[00652] The title product was prepared from 1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolane]-2(3H)-one (Intermediate 70) according to the method described in Example 47. MS (ESI) m/z 419.2 (M+H)*.

Example 64 8-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl-4H-1,2,A]triazolo[4,3-a][1]benzazepin-S5(6H) -one CC Ox

[00653] The title product was prepared from 8*-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane -2,5'-[1,2 A]triazolo[4,3-a][1]benzazepine] (Example 62) according to the method described in Example 48. MS (ESI) m/z 453.0 ( M+H)*.

Example 65 8-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a] [1]benzazepin-5-ol

[00654] The title product was prepared from 8-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4H-[1,2,4]triazolo[4,3-a ][1 Ibenzazepine-5(6H)-one (Example 64) according to the method described in Example 49. MS (ESD m/z 457.1 (M+H)*.

Example 66 1º-[trans-4-(pyridin-2-yloxy)cyclohexyl]|-4º H,6º H-spiro[1,3-dioxolane-2,5*-[1,2,4]triazolo[ 4,3-a][1]benzazepine]-8'-carbonitrile

233 /323 Rim:

[00655] A mixture of 49.7 mg (0.1 mmol) of 8º-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]|-4'H,6'H-spiro [1,3-dioxolane-2.5"-[1,24]triazolo[4,3-a][1|benzazepine] (Example 62), 13.4 mg (0.15 mmol) copper cyanide (I) and 0.6 mL of dry DMF, under microwave irradiation conditions in a CEM Explorer microwave reactor, was stirred at 220°C for 30 minutes. The reaction mixture was diluted with dichloromethane, filtered through Celite, washed with dichloromethane. The filtrate was concentrated and ethyl acetate and aqueous ammonia solution were added to the residue. The phases were separated, the organic phase was washed once with aqueous ammonia, dried over anhydrous NaSO, filtered and concentrated. The residue was purified by reversed-phase chromatography using acetonitrile:water containing 1% trifluoroacetic acid=1:1 as eluent. Thus, 17.8 mg (40%) of the title product was obtained. MS (ESID) m/z 444, 2 (M+H)*.

Example 67 (5S)-8-chloro-N,N-dimethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl-5,6-dihydro-4H-1,2,A4] triazolo[4,3-a][1]benzazepine-S-amine Ss O, /

[00656] The title product was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepine-5-amine (Example 7) according to the method described in Example 22. Ieion = -36.8° (c=0.1; methanol); MS (ESI) m/z 438.2 (M+H)*.

Example 68 (5S)-N-(8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-

234 / 323 dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepin-5-ylYacetamide C' Qd O, LÁ;

[00657] The title product was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepine-5-amine (Example 7) according to the method described in Example 9. Erg= -24.3° (c=0.1; methanol); MS (ESI) m/z 452.2 (M+H)*.

Example 69 8º -Chloro-1"-[trans-4-(piperidin-1-ylmethyl)cyclohexyl]-VH,6ºH-spiro[1,3-dioxolane-2.5"-[1,2,4] triazolo[4,3-a][1]benzazepine quo cr O

[00658] The title product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolane]-2(3H)-one (Intermediate 53) and trans-4-(piperidin-1-ylmethyl)cyclohexane carboxylic acid hydrazide (Intermediate 65) according to the method described in Example 47. MS (ESD) m/z 457.2 (M+H)*.

Example 70 trans-4-(8*-chloro-4ºH,6'ºH-spiro[1,3-dioxolane-2.5"-1,2,A]triazolo[4,3-a][1]benzazepine ]-1"-iD)cyclohexyl |(pyrrolidin-1-iDmethanone or O cr LS

[00659] The title product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolane]-2(3H)-one (Intermediate 53) and trans-4-(pyrrolidin-1-ylcarbonyl)cyclohexane carboxylic acid hydrazide

235 / 323 (Intermediate 78) according to the method described in Example 47. MS (ESD m/z 457.2 (M+H)*.

Example 71 8-Chloro-1-[trans-4-(trifluoromethylcyclohexyl --4H-[1,2,4-triazolo[4,3-a][1]|benzazepin-5(6H)-one

[00660] The title product was prepared from 8'-chloro-1"-[trans-4-(trifluoromethyl)cyclohexyl]-4th H,6'H-spiro[1,3-dioxolane-2,5 '-[1,24]triazolo[4,3-a][1Ibenzazepine] (Example 61) according to the method described in Example 48. MS (ESI) m/z 384.1 (M+H)* .

Example 72 8-Chloro-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine -5-ol

[00661] The title product was prepared from 8-chloro-1-[trans-4-(trifluoromethyl)cyclohexyl]-4H-[1,2,A4]triazolo[4,3-a][1] benzazepine-S5(6H)-one (Example 71) according to the method described in Example 49. MS (ESD m/z 386.1 (M+H)*.

Example 73 (cis)-8-(8*-chloro-4"H,6º H-spiro[1,3-dioxolane-2,5º-[1,2,4 triazolo[4,3-a][1] benzazepine]-1"-yl)-3-methyl-1-oxa-3-azaspiro[4.5]decan-2-one

236 / 323

XY "O ; x Ls

[00662] The title product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolane]-2(3H)-one (Intermediate 53) and (cis)-3-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-8-carboxylic acid hydrazide (Intermediate 87) according to the method described in Example

47. MS (ESD m/z 445.2 (M+H)*. Example 74 8-Chloro-S5-methoxy-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro -4H- 1,24 ttriazolo[4,3-a][1]benzazepine

NZ

[00663] The title product was prepared from 8-chloro-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4 ,3-a][1]benzazepin-5-ol (Intermediate 72) according to the method described in Example 50. MS (ESI) m/z 400.1 (M+H)*. Example 75 (trans)-8-(8*-chloro-4' H,6º H-spiro[1,3-dioxolane-2.5"º-1,2,A4]triazolo[4,3-a][ 1]benzazepin]-1"-II)-3-methyl-1-oxa-3-azaspiro 4,5 decan-2-one “AO o . It's Ls

[00664] The title product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolane]-2(3H)-one (Intermediate 53)

237/323 and (trans)-3-methyl-2-oxo-1-oxa-3-azaspiro[4,5-decane-8-carboxylic acid hydrazide (Intermediate 86) according to the method described in Example

47. MS (ESD m/z 445.1 (M+H)*. Example 76 N-((5S)-8-chloro-1-[trans -4-(pyridin-2-yloxy)cyclohexyl]- 5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1]benzazepin-5-yl)-N-methyl methanesulfonamide

SS AO. a) N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2A]triazole [4,3-a Ud Ibenzazepin-5-yl |methanesulfonamide * e s. so

[00665] To a solution of 204 mg (0.5 mmol) of (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro -4H-[1,2 A]triazolo[4,3-a][1]benzazepine-5-amine (Example 7) and 5 mL of pyridine, 46 uL (70.6 mmol) of methanesulfonyl chloride were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane, washed with NaHCO solution; and saturated NaCl solution, the organic phase was dried over anhydrous Na2SO, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 90 mg (37%) of the title product was obtained. MS (ESI) m/z 488.3 (M+H)*. b) N-[(55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2A]triazolo[4 ,3-a][1 Ibenzazepin-5-yl |-N-methylmethanesulfonamide

238 / 323

[00666] The title product was prepared from N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H -[1,2A]triazolo[4,3-a][1]benzazepin-5-1l)|methanesulfonamide (step a) of Example 76) according to the method described in Example 19. MS (ESI) m/ z 502.2 (M+H)*.

Example 77 (5S)-8-chloro-N-ethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4] triazolo[4,3-a][1]benzazepine-5-amine o. a) 1(5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2 Altriazolo[4,3-a ][1 Ibenzazepin-5-yl | tert-butyl carbamate E e.g.

[00667] To a solution of 204 mg (0.5 mmol) of (55S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro -4H-[1,2 A]triazolo[4,3-a][1]benzazepine-5-amine (Example 7) and 10 mL of dichloromethane 275 uL (1.5 mmol) DIPEA and 130 mg (0.6 mmol) di-fert-butyl dicarbonate were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with NaHCO solution; and water, the organic phase was dried over NaSO, anhydrous, filtered and concentrated. Thus, 246 mg (97%) of the title product was obtained. MS (ESI) m/z 510.2 (M+H)*. b 1(5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2A]triazolo[4,3- a][1|benzazepin-5-1yl tert-butyl jetylcarbamate AO. er da

239 / 323

[00668] The title product was prepared from ((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A]triazolo[4,3-a][1]benzazepin-5-11]fert-butyl carbamate (step a) of Example 77) according to the method described in step a) of Example 23. MS (ESI) m/z 538.2 (M+H)*. c) (55)-8-chloro-N-ethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl |-5,6-dihydro-4H-1,2A]triazolo[ 4,3-a][1]benzazepine-5-amine

[00669] The title product was prepared from ((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A]triazolo[4,3-a][1]benzazepin-5-yl tert-butyl jetylcarbamate (step b) of Example 77) according to the method described in Example 6. MS (ESI) m/ z 438.3 (M+H)*.

Example 78 (5S)-8-Chloro-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2,4-Ytriazolo[ 4,3-a][1]benzazepine-5-amine * a) [(5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di -hydro-4H- 1,2 A]triazole 4,3-a])| 1]benzazepin-5-yl]tert-butyl methylcarbamate AO. " /

[00670] The title product was prepared from ((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A]triazolo[4,3-a][1]benzazepin-5-11]fert-butyl carbamate (step a) of Example 77) according to the method described in step a) of Example 21. MS (ESI) m/z 524.3 (M+H)*. b 5,5)-8-chloro-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4]triazole [4,3-a][1 Ibenzazepine-5-amine

240 / 323

[00671] The title product was prepared from ((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A]triazolo[4,3-a][1]benzazepin-5-11]tert-butyl methylcarbamate (step a) of Example 78) according to the method described in Example 6. MS (ESI) m /z 424.2 (M+H)*.

Example 79 8º -chloro-1"-[1-(pyrimidin-2-iDazetidin-3-yl-VP H,6'H-spiro[1,3-dioxolane-2,5º-[1,2,4]triazole [4,3-a][1]benzazepine

Mr

[00672] The title product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolane]-2(3H)-one (Intermediate 53) and 1-(pyrimidin-2-yl)azetidin-3-carboxylic acid hydrazide (Intermediate 82) according to the method described in Example 47. MS (ESI) m/z 411.1 (M+H)*.

Example 80 N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazole [4,3-a][1]benzazepin-5-yl)-4-fluorobenzamide No “O

[00673] To a solution of 204 mg (0.5 mmol) of (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro -4H-[1,2 A]triazolo[4,3-a][1]benzazepine-5-amine (Example 7) and 3 mL of pyridine, 90 uL (0.76 mmol) of 4-fluorobenzoyl chloride were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was

241/323 then diluted with ethyl acetate, washed with water, the organic phase was dried over Na 3 SO, anhydrous, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 155 mg (58.5%) of the title product was obtained. [033= -69.8° (c=0.1; methanol); MS (ESI) m/z 532.2 (M+H)*.

Example 81 8º-bromo-1-[trans-4-(trifluoromethyl)cyclohexyl--4H,6ºH-spiro) 1,3-dioxolane-2.5”-1,2,A]triazolo[4,3 -a][1]benzazepine

[00674] The title product was prepared from 7-bromo-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolane]-2(3H)-one acid hydrazide ( Intermediate 36) and trans4-(trifluoromethyl)cyclohexane-carboxylic acid (Intermediate 55) according to the method described in Example 47. MS (ESD m/z 472.1 (M+H)*.

Example 82 S-(propan-2-ylamino)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4] trifluoroacetate triazolo[4,3-all benzazepin-8S-carbonitrile

[00675] The title product was prepared from 8-bromo-N-(propan-2-11)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di- hydro-4H-[1,24]triazolo[4,3-a][1Ibenzazepine-S-amine (Example 40) according to the method described in Example 66. MS (ESI) m/z 443.3 ( M+H)*.

Example 83

242 / 323 (SS)-8-chloro-N-(4-fluorobenzyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepine-5-amine =

[00676] To a solution of 204 mg (0.5 mmol) of (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro -4H-[1,2A]triazolo[4,3-al[1]benzazepine-5-amine (Example 7) and 5 mL of DMF, 30 mg (0.75 mmol) of sodium hydride (oil dispersion at 60%) were added and the reaction mixture was stirred at room temperature for 15 minutes. Then, 90 µl (0.75 mmol) of 4-fluorobenzyl chloride was added and stirred at room temperature overnight. At this time, the reaction mixture was diluted with ethyl acetate, washed with water, the organic phase was dried over NaSO, anhydrous, filtered and concentrated. The residue was purified by column chromatography using dichloromethane:methanol=9:1 as eluent. Thus, 55 mg (21%) of the title product was obtained.

[0] 3º=-22.1º (c=0.1; methanol); MS (ESID) m/z 518.3 (M+H)*.

Example 84 1st -[trans -4-(trifluoromethylcyclohexyl]|-4th H,6th H-spiro[1,3-dioxolane-2,5'-12,4 triazolo[4,3-a][1]benzazepine ]-8' -carbonitrile

PO “O

[00677] The title product was prepared from 8º*-bromo-1-[trans-4-(trifluoromethyl)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5 "- [1,2 4]triazolo[4,3-a][1 Ibenzazepine] (Example 81) according to the method

243 / 323 described in Example 66. MS (EST) m/z 419.2 (M+H)*.

Example 85 trans-4-(8"-bromo-4ºH,6'H-spiro[1,3-dioxolane-2,5'-1,2,A]triazolo[4,3-a][1]benzazepin] -1"-iD)cyclohexyl|(piperidin-1-iDmethanone o G Jd O, No

[00678] The title product was prepared from 7-bromo-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolane]-2(3H)-one (Intermediate 36) and trans-4-(piperidin-1-ylcarbonyl)cyclohexane carboxylic acid hydrazide (Intermediate 97) according to the method described in Example 62. MS (ESD m/z 517.2 (M+H)*.

Example 86 methyl trans-4-(8-bromo-5-OxO-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-all benzazepin-1-yl]cyclohexane carboxylate and Example 87 8-bromo-1-[trans-4-(piperidin-1-ylcarbonylD)cyclohexyl]-4H - 1,2,A4]triazolo 4,3-a] 1]benzazepin-5(6H)- ona O Jd A

THE

[00679] A mixture of 118 mg (0.23 mmol) of [trans-4-(8'-bromo-4° H,6'H-spiro[1,3-dioxolane-2,5'-[1,2] ,4]triazolo[4,3-a][1]benzazepin]-1"-

244 / 323 yl)cyclohexyl J(piperidin-1-yl)]methanone (Example 85), 3.1 mL of methanol and 4.7 mL of concentrated hydrochloric acid was refluxed for 2.5 hours, then cooled to room temperature. environment. The pH of the reaction mixture was adjusted to basic with 10% K3CO solution; and extracted with dichloromethane, the combined organic phases were dried over anhydrous Na 7 SO, filtered and concentrated. The residue was purified by column chromatography using ethyl acetate:methanol=4:1 as eluent. Concentration of the first fraction gave 17 mg (18% trans4-(8-bromo-5-oxO-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1 Ibenzazepin- Methyl 1-yl)cyclohexane carboxylate (Example 86) MS (ESI) m/z 420.1 (M+H)* Concentration of the second fraction gave 35 mg (32%) of 8-bromo-1- [trans-4-(piperidin-1-ylcarbonyl)cyclohexyl]-4H-[1,2A4]triazolo[4,3-a][1]benzazepin-S(6H)-one (Example 87). (ESID) m/z 471.1 (M+H)*.

Example 88 8º -chloro-L1 -[trans -4-(trifluoromethyl)cyclohexyl -4' H,6º H-spiro)| 1,3-dioxane-2,5*-1,2,A4]triazolo[4,3-a][1]benzazepine

O and D

[00680] The title product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxane]-2(3H)-one (Intermediate 98) according to the method described in Example 47. MS (ESI) m/z 467.2 (M+H)*.

Example 89 1º-[trans-4-(piperidin-1-ylcarboniD)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5º-[1,2,4]triazolo[ 4,3-a][1]benzazepin]-8"-carbonitrile

245 / 323

[00681] The title product was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxane]-2(3H)-one (Intermediate 98) and hydrazide! of trans-4-(trifluoromethyl)cyclohexane-carboxylic acid (Intermediate 55) according to the method described in Example 47. MS (ESD m/z 442.1 (M+H)*.

Example 90 8º -chloro-1"-[trans-4-(pyridin-2-yloxy)cyclohexyl-2H,6ºH-spiro)| 1,3-dioxane-2,5*-1,2,A4] triazolo[4,3-a][1]benzazepine

FO No.

[00682] The title product was prepared from [trans-4-(8'-bromo-4th H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazole [4,3-a][1]benzazepin]-1"-yl)cyclohexyl J(piperidin-1-yl)]methanone (Example 85) according to the method described in Example 66. MS (ESI) m /z 462.2 (M+H)*.

Example 91 8-bromo-1-[trans-4-(trifluoromethyl)cyclohexyl-4H-1,2A]triazolo[4,3-a][1]benzazepin-5(6H)-onone FO,

[00683] The title product was prepared from 8'-bromo-1'-[trans-4-(trifluoromethyl)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2, 5"- [1,2 4]triazolo[4,3-a][1 Ibenzazepine] (Example 81) according to the method

246 / 323 described in Example 48. MS (EST) m/z 429.2 (M+H)*.

Example 92 trans-4-(8-bromo-5-hydroxy-5,6-dihydro-4H-1,2A]triazolo 4,3-al[1]benzazepin-1-yl)cyclohexyl]( piperidin-1-yl)]|methanone “a

[00684] The title product was prepared from 8-bromo-1-[trans-4-(piperidin-1-ylcarbonyl)cyclohexyl]-4H-[1,2,4]triazolo[4,3-a ][1]|benzazepine-5(6H)-one (Example 87) according to the method described in Example 49. MS (ESD m/2 473.1 (M+H)*.

Example 93 8-bromo-1-[trans-4-(trifluoromethylcyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo 4,3-a][1]benzazepin-5-ol “The Co

[00685] The title product was prepared from 8-bromo-1-[trans-4-(trifluoromethyl)cyclohexyl]-4H-[1,2,4]triazolo[4,3-a][1 Ibenzazepine -5(6H)-one (Example 91) according to the method described in Example 49. MS (ESD) m/z 432.0 (M+H)*.

Example 94 1º-(1,4"-bipiperidin-1"-yl)-8*-chloro-4' H,6º H-spiro[1,3-dioxolane-2,5*-[1,2,4] triazolo[4,3-a][1]benzazepine

CC = Ls

[00686] A mixture of 60 mg (0.168 mmol) of 1º-bromo-8'-chloro-

247 /323 4th H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine] (Intermediate 96) and 255 mg (1.514 mmol) of 4-piperidinepiperidine was stirred at 130-140°C for 3-4 hours under argon. After cooling to room temperature, it was purified by column chromatography using dichloromethane:methanol:ammonium hydroxide=18:1:0.1 as eluent. The resulting crude product was further purified on a preparative TLC plate using dichloromethane:methanol:ammonium hydroxide=18:1:0.1 as eluent. Thus, 20.5 mg (27%) of the title product was obtained. MS (ESI) m/z 444.2 (M+H)*.

Example 95 1-(1,4”-bipiperidin-1”-yl)-8-chloro-5,6-dihydro-4H-1,2A]triazolo*-a][1]benzazepin-5-yl |ferc-butyl carbamate

[00687] The title product was prepared from (1-bromo-8-chloro-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepin- tert-butyl 5-yl)carbamate (Intermediate 94) according to the method described in Example 94. MS (ESD m/z 501.3 (M+H)*.

Example 96 8º -Fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl|-4'H,6'H-spiro) 1,3-dioxolane-2.5"-1,2, A]triazolo[4,3-a][1]benzazepine F 1 GS

[00688] The title product was prepared from 7-fluoro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolane]-2(3H)-one (Intermediate 92) according to the method described in Example 47. MS (ESI) m/z 437.3 (M+H)*.

Example 97 (5S)-8-chloro-N-(4-fluorobenzyl)-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di- hydro-4H-[1,2,A4]triazolo[4,3-a][1]benzazepin-5-amine O. CC ' »

[00689] The title compound was prepared from (55)-8-chloro-N-(4-fluorobenzyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6- dihydro-4H-[1,24]triazolo[4,3-a][1]benzazepin-5-amine (Example 83) and iodomethane according to the method described in Step a) of Example 21. = -68.7° (c=0.1; methanol); MS (ESI) m/z 532.3 (M+H)*.

Example 98 N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepin-5-ylprop-2-enamide & O

[00690] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and acrylic acid according to the method described in Step a) of Example 10. Er) 3°= -24° (c =0.1; methanol); MS (EST) m/z 464.2 (M+H)*.

Example 99 (SR)-8-chloro-N-ethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4] triazolo[4,3-a][1]benzazepin-5-amine

249 / 323 NO. aea) 1(5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl |-5,6-dihydro-4H-1,2A]triazolo[4,3 -a][1]benzazepin-5-yl |tert-butyl carbamate E o TO, LO.

[00691] A mixture of 400 mg (0.976 mmol) of (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- [1,2 A]triazolo[4,3-al[1]benzazepin-5-amine (Example 8), 20 mL of dichloromethane, 260 mg (1.19 mmol) of di-tert-butyl dicarbonate and 0. 55 mL (3.16 mmol) of NN-diisopropylethylamine was stirred at room temperature for 18 h, then diluted with dichloromethane and water, the organic layer was separated and the water phase was extracted with dichloromethane. The combined organic phases were dried over NaSO3, filtered and concentrated to give 500 mg (100%) of the title compound, which was used in the next step without further purification. b LSR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2A]triazole 4,3-al| 1]benzazepin-5-yl | tert-butyl ethylcarbamate

SS FT Up,

CO cr E

[00692] The title compound was prepared from ((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A]triazolo[4,3-a][1]benzazepin-5-yl]fert-butyl carbamate (Step a) of Example 99) and ethyl iodide according to the method described in Step a) of Example 21. MS (ESID) m/z 538.3 (M+H)*. c) (5R)-8-chloro-N-ethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2A]triazolo[ 4,3-a][1 Ibenzazepin-5-amine

250 / 323

[00693] The title compound was prepared from ((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A]triazolo[4,3-a][1]benzazepin-5-1l Fert-butyl jetylcarbamate (Step b) of Example 99) according to the method described in Example 6. 192= +23.1° (c=0.1; methanol); MS (ESI) m/z 438.1 (M+H)*.

Example 100 (SR)-8-chloro-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4] triazolo[4,3-a][1]benzazepin-5-amine

C 7 = a) L(5SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2A ]triazolo[ 4,3-a][1]benzazepin-5-1l | tert-butyl methylcarbamate & x

I A

[00694] The title compound was prepared from ((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A]triazolo[4,3-a][1]benzazepin-5-11[tert-butyl carbamate (Step a) of Example 99) and iodomethane according to the method described in Step a) of Example 21 MS (ESD m/z 524.3 (M+H)*. b) (5R)-8-chloro-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]- 5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1|benzazepin-5-amine

[00695] The title compound was prepared from ((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2 A]triazolo[4,3-a][1]benzazepin-5-1l |]| tert -butyl methylcarbamate (Step a) of Example 100) according to the method described in Example 6. Nav= + 21.4° (c=0.1; methanol); MS (ESI) m/z 424.1 (M+H)*.

Example 101

251 /323 6GR)-8-chloro-N,N-dimethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl-5,6-dihydro-4H-1,2,A] triazolo[4,3-a][1]benzazepin-5-amine POR,

OO and ”

[00696] A mixture of 5.93 g (14.5 mmol) of (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di- hydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8), 11 ml of 37% solution of formaldehyde in water, 100 ml of methanol and 65 mL of dichloromethane was cooled to 5°C and 15.9 g (75 mmol) of sodium triacetoxyborohydride was added to the reaction mixture at such a rate to keep the internal temperature below 5°C. After the addition was complete, the reaction mixture was stirred at room temperature for 5 h, then concentrated. The residue was dissolved in water and the pH adjusted to 8 by adding 10% NaOH solution. The precipitated product was filtered, washed with water and dried to give 5.75 g (91%) of the title compound. [dfB= +25.6° (c=0.1; methanol); MS (ESD m/z 438.2 (M+H)*.

Example 102 1-[trans-4-(pyridin-2-yloxy)cyclohexyl |-4H - 1,2A]triazolo 4,3-a) 1]benzazepin-5(6H)-one

NS

[00697] The title compound was prepared from 1'-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5 '-[1,24]triazolo[4,3-a][1Ibenzazepine] (Example 63) according to the method described in Example 48. MS (ESI) m/z 375.1 (M+H)* .

Example 103 (5S)-8-chloro-S-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclo-

252 /323 hexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine

CS" = and Example 104 (5R)-8-chloro-5-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1, 2,4]triazolo[4,3-a][1]benzazepine

CS" -

[00698] The title compounds were obtained from 8-chloro-5-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]racemic benzazepine (Example 58) by chiral preparative HPLC (CHIRALPAK IA 20 µm preparative stationary phase; 2.5Xx20cm; F=18mL/min; eluent: methyl ether of tert-butyl: dichloromethane: ethanol = 85:10:5; isocratic; t=25°C). The first compound eluting was the (58) enantiomer (T, 15.4 min; fu]Z, = +11.8º (c=0.1; chloroform); Example 103) and the second eluting compound was the enantiomer (SR ) (T, 21.5 min; [o 2 =-12.0° (c=0.1; chloroform); Example 104). The absolute configuration of the compounds was determined by VCD spectroscopy.

Example 105 8-Chloro-5-(propan-2-yloxy)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2, 4]triazolo[4,3-a][1]benzazepine No O, OO.

[00699] A mixture of 100 mg (0.243 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 ,A4]triazolo[4,3-

253 / 323 a][1]benzazepin-5-ol (Example 55), 5 mL of DMF and 12.7 mg (0.316 mmol) of 60% sodium hydride in mineral oil was stirred at 0°C for 30 min, then 52 .4 µL (0.316 mmol) of diisopropyl sulfate was added and the reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with water, extracted with ethyl acetate, the combined organic layers washed with brine, dried over NaSO4 , filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane : methanol = 95:5 as eluent to give 32 mg (29%) of the title compound. MS (ESI) m/z 453.2 (M+H)*.

Example 106 8'-Chloro-1'-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'H-spiro)| 1,3-dioxep: ane-2.5"- 1,2,A4]triazolo[4,3-a][1]benzazepine

CO or dO)

[00700] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxepan]-2(3H)-one — (Step c ) of Intermediate 104) according to the method described in Example 47. MS (ESD m/z 481.2 (M+H)*.

Example 107 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2A]triazolo 4,3-a]1]benzazepin-5-ol

[00701] The title compound was prepared from 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4H-[1,2,A]triazolo[4,3-a][1] benzazepin-S5(6H)-one (Example 102) according to the method described in Example 49. MS (ESID) m/z 377.2 (M+H)*.

254 / 323 Example 108 trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4-triazolo[4,3-a] [1 benzazepin =-1'-iDcyclohexyl)(morpholin-4-yl)]methanone DO, ar 1 SS

[00702] Under argon to a mixture of 100 mg (0.39 mmol) of 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolan]-2(3H )-one (Intermediate 53) and 10 mL of dichloromethane, 3 uL (0.04 mmol) of trifluoroacetic acid and 70 mg (0.47 mmol) of trimethyloxonium tetrafluoroborate were added. The reaction mixture was stirred at room temperature for 6 h, then 151 mg (0.59 mmol) of trans-4-(morpholin-4-ylcarbonyl)cyclohexane carbohydrazide (Intermediate 79) and 10 mL of acetonitrile were added and the mixture was refluxed for 8 h. After concentration, the residue was purified by flash column chromatography using dichloromethane:methanol:ammonium hydroxide solution = 180:10:1 as eluent to give 72 mg (39%) of the title compound. MS (ESI) m/z 473.2 (M+H)*.

Example 109 S-Methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazole) 4,3-a][ 1]benzazepine

[00703] The title compound was prepared from 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24]triazolo[4, 3-a][1]benzazepin-5-ol (Example 107) according to the method described in Example 50. MS (ESI) m/z 391.2 (M+H)*.

Example 110 8-Fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4H -

255 / 323 1,2,A]triazolo) 4,3-a] 1]benzazepin-5(6H)-one

[00704] The title compound was prepared from 8'-fluoro-1"-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'H-spiro[1,3- dioxolane-2.5"-[1,24]triazolo[4,3-a][1Ibenzazepine] (Example 96) according to the method described in Example 48. MS (EST) m/z 393.3 ( M+H)*.

Example 111 8-Fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo 4,3-a 1]benzazepin -5-ol vo is

[00705] The title compound was prepared from 8-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4H-[1,2,A4]triazolo[4,3-a ][1]benzazepin-5(6H)-one (Example 110) according to the method described in Example 49. MS (ESD m/z 395.2 (M+H)*.

Example 112 [8-Chloro-1-[trans-4-(morpholin-4-i)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a ][1]tert-butyl benzazepin-5-yl carbamate o

[00706] The title compound was prepared from tert-butyl (7-chloro-2-OxO-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate (Intermediate 5 ) and trans-4-(morpholin-4-yl)cyclohexane-carbohydrazide (Intermediate 81) according to the method described in Method B of Example 5. MS (ESD) m/z 502.2 (M+H) *.

Example 113 8-Chloro-1-[trans-4-(morpholin-4-yl)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3 -a][1]benzazepin-5-amine “Oo q

[00707] The title compound was prepared from (8-chloro-1-[trans-4-(morpholin-4-11)cyclohexyl]-5,6-dihydro-4H-[1,2, A4]triazolo[4,3-a][1]benzazepin-5-yl] tert-butyl carbamate (Example 112) according to the method described in Example 6. MS (ESI) m/z 402.1 (M +H)* Example 114 8-Chloro-1-[trans-4-(morpholin-4-iD)cyclohexyl -- V-(propan-2-yl)-5,6-dihydro-4H- [1,2,4]triazolo[4,3-a][1]benzazepin-5-amine * VW Co MÁ,

[00708] The title compound was prepared from tert-butyl 8-chloro-1-[trans-4-(morpholin-4-yl)cyclohexyl]-5,6-dihydro-4H-[1, 2 A4]triazolo[4,3-a][1]benzazepin-5-amine (Example 113) according to the method described in Example 24. MS (ESI) m/z 444.2 (M+H)*. Example 115 Gr,8r)-8-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-1,2,A4]triazolo[4,3-a] [1]benzazepin]-1'-yl)-2-(propan-2-yl)-2-azaspiro 4.5 Person SO rO

257 /323

[00709] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and (5r,8r)-1-OxO-2-(propan-2-11)-2-azaspiro[4,5]decane-8-carbohydrazide (Intermediate 102) according to the method described in Example 62. MS (ESD m/z 471.2 (M+H)*.

Example 116 (Sr,8r)-8-(8-chloro-5-hydroxy-5,6-dihydro-4H -[1,2,A4]triazolo 4,3-a][1-benzazepin-1-yl )-2-(propan-2-yl)-2-azaspiro 4,5] decan-1-one "TO, a) 8-chloro-1-[(5r,8r)-1-0xO-2-(propan -2-yl)-2-azaspiro[4.5]dec-8-11]-4H-1,2 A]triazolo[4,3-a][1 Ibenzazepin-S(6H)-one

YO *X<O

[00710] The title compound was prepared from (5r,8r)-8-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2 ,4]triazolo[4,3-a][1]benzazepin])-1"-yl)-2-(propan-2-11)-2-azaspiro[4.5]decan-1-one (Example 115 ) according to the method described in Example 48. MS (ESI) m/z 427.3 (M+H)*.b 5r,8r)-8-(8-chloro-5-hydroxy-5,6-di -hydro-4H-[1,2,A4]triazolo 4,3-al[1]benzazepin-1-11)-2-(propan-2-yl)-2-azaspiro[4.5 |decan-1- onea

[00711] The title compound was prepared from 8-chloro-1-[(5r,8r)-1-OxO-2-(propan-2-yl)-2-azaspiro[4.5]dec-8- 11]-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5(6H)-one (Step a) of Example 116) according to the method described in Example 49. MS (ESI) m/z 429.1 (M+H)*.

Example 117 (5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]|-5-(pyrrolidin-1-yl)-5,6-dihydro-4H- [1,2,4]triazolo[4,3-a][1]benzazepine

258 / 323 cu

OF

[00712] A mixture of 400 mg (0.976 mmol) of (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- [1,2 A]triazolo[4,3-al[1]benzazepin-5-amine (Example 7), 20 mL of DMF, 117 uL (0.98 mmol) of 1,4-dibromobutane and 954 mg (2 .93 mmol) of Cs;CO; was stirred at 40°C for 24 h, then concentrated. The residue was dissolved in water and extracted with ethyl acetate. The combined organic phases were dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane:methanol = 95:5 as eluent to give mg (8%) of the title compound. MS (ESI) m/z 464.3 (M+H)*.

Example 118 N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepin-5-yl)-2,2-dimethyl propanamide o *y NO,

[00713] A mixture of 82 mg (0.2 mmol) of (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro- 4H-[1,24]triazolo[4,3-al[1]benzazepin-5-amine (Example 7), 5 mL of dichloromethane, 35 uL (0.25 mmol) of triethylamine and 30 uL (0.24 mmol) of trimethylacetyl chloride was stirred at room temperature for 3 h, then diluted with dichloromethane and successively washed with NaHCO solution; saturated and brine. The organic phase was dried over NaSO₄, filtered and concentrated to give 93 mg (94%) of the title compound. [es=-32.1° (c=0.1; methanol); MS (ESI) m/z 494.3 (M+H)*.

Example 119 N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2, A4]triazolo[4,3-a][1]benzazepin-5-ylcyclopropane carboxamide AO.

with

[00714] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and cyclopropanecarboxylic acid according to the method described in Step a) of Example 10. * julii=-45.3° (c =0.1; methanol); MS (ESI) m/z 478.3 (M+H)*.

Example 120 N(5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo 4,3 -a][1]benzazepin-5-yl)-2-methylpropanamide Ss

TS C LOL

[00715] or

[00716] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-al[1]benzazepin-5-amine (Example 7) and isobutyric acid according to the method described in Step a) of Example 10. [a]ã= -30.6° ( c=0.1; methanol); MS (EST) m/z 480.3 (M+H)*.

Example 121 N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepin-5-ylYcyclobutane carboxamide

260 / 323 AO.

[00717] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and cyclobutanecarboxylic acid according to the method described in Step a) of Example 10. Evtff=-39.3° (c= 0.1; methanol); MS (ESI) m/z 492.3 (M+H)*. Example 122 (S5S)-8-chloro-5-(morpholin-4-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl|-5,6-dihydro-4H-[ 1,2,A4]triazolo[4,3-a][1|benzazepine CC Or nO

THERE CO

[00718] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and bis(2-iodoethyl)ether according to the method described in Example 117. MS (ESI) m/z 480 .2 (M+H)*. Example 123 N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepin-5-11)-2,2-dimethyl propanamide oy O.

[00719] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) according to the method described in

261 /323 Example 118. [a]º= +21.6º (c=0.1; methanol); MS (ESI) m/z 494.2 (M+H)*.

Example 124 N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4 triazole 4 ,3-a][1]benzazepin-5-yl)-2-methylpropanamide

SS do, LÉ,

[00720] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and isobutyric acid according to the method described in Step a) of Example 10. [a]sº= +29.4º (c=0.1; methanol); MS (ESD m/z 480.2 (M+H)*.

Example 125 N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazole [4,3-a][1]benzazepin-5-yl)cyclobutane carboxamide AO.

Co CO and er

[00721] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-al[1]benzazepin-5-amine (Example 8) and cyclobutanecarboxylic acid according to the method described in Step a) of Example 10. EJff=+29.8° (c=0 .1; methanol); MS (ESI) m/z 492.2 (M+H)*.

Example 126 N-[(5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepin-5-ylYcyclopropane carboxamide

262 / 323 AO.

LAO PR

[00722] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and cyclopropanecarboxylic acid according to the method described in Example 10, Step a). 5th (c=0.1; methanol); MS (ESI) m/z 478.2 (M+H)*. Example 127 (5S)-8-chloro-5-(piperidin-1-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2,A4]triazolo[4,3-a][1]benzazepine

THE

[00723] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and 1,5-dibromopentane according to the method described in Example 117. MS (ESI) m/z 478.4 (M+H)*. Example 128 (S5S)-N-(butan-2-yl)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2,4]triazolo[4,3-a][1]benzazepin-5-amine NO. &

CO º if

[00724] The title compound was prepared from (5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and 2-butanone according to the method described in Example 24. MS (EST) m/z 466.4 (M +H)*.

263 / 323 Example 129 (Ss, 8s5)-8-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-1,2,A4]triazolo[4, 3-a][1]benzazepin]-1'-yl)-2-(propan-2-yl)-2-azaspiro[4.5]decan-1-one uu "C<O

[00725] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and (5s,8s)-1-OxO-2-(propan-2-11)-2-azaspiro[4.5]decane-8-carbohydrazide (Intermediate 101) according to the method described in Example 62. MS ( ESD m/z 471.2 (M+H)*.

Example 130 8-Chloro-5-methoxy-1-[trans-4-(morpholin-4-iDcyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3- a][1]benzazepine or

[00726] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepine-2-thione (Step e) of Intermediate 103) and trans -4-(morpholin-4-yl)cyclohexane carbohydrazide (Intermediate 81) according to the method described in Step a) of Example 37. MS (ESI) m/z 417.3 (M+H)*.

Example 131 8-Chloro-5-ethoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4, 3-a][1]benzazepine

264 / 323

DSO À > LO.

[00727] The title compound was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4 ]triazolo[4,3-a][1]benzazepin-5-ol (Example 55) and ethyl iodide according to the method described in Example 50. MS (EST) m/z 439.3 (M+H) *.

Example 132 (SR)-8-chloro-S-methoxy-1-[trans-4-(trifluoromethyl)cyclohexyl-5,6-dihydro-4H-1,2,4]triazolo[4,3 -a][1]benzazepine

TO THE . Example 133 (5S)-8-chloro-S-methoxy-1-[trans-4-(trifluoromethyl)cyclohexyl-5,6-dihydro-4H-1,2,A4]triazolo[ 4,3-a][1]benzazepine F.

"Hey,

[00728] The title compounds were obtained from 8-chloro-5-methoxy-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2A] triazolo[4,3-a][1]benzazepine racemic (Example 74) by chiral preparative HPLC (CHIRALPAK IG 20 µm preparative stationary phase; 1.6x25cm; F=12mL/min; eluent: tert-butyl methyl ether: dichloromethane: ethanol = 90:8:2; isocratic; t=25°C). Optical rotation of the first compound eluting (T, 18.0 min) was neither = +15.6° (c=0.1; chloroform); and that of the second compound eluting (T, 23.3 min) was Ts = -13.5° (c=0.1; chloroform). THE

The absolute configuration of the compounds was not determined. Example 134 8-Fluoro-S-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-S,6-dihydro-4H-[1,2,4-triazolo[4,3 -a][1]benzazepine

OF AND

[00729] The title compound was prepared from 8-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4 ]triazolo[4,3-a][1]benzazepin-5-ol (Example 111) according to the method described in Example 50. MS (ESI) m/z 409.3 (M+H)*. Example 135 8-Chloro-N-(propan-2-yl)-1-[1-(pyridin-2-i)piperidin-4-yl]-5,6-dihydro-4H-[1,2, A4]triazolo[4,3-a][1]benzazepin-5-amine or A,

[00730] The title compound was prepared from 8-chloro-1-[1-(pyridin-2-yl)piperidin-4-yl]-5,6-dihydro-4H-[1,2,4 ]triazolo[4,3-a][1]benzazepin-5-amine (Example 2) according to the method described in Example 24. MS (ESID) m/z 437.4 (M+H)*. Example 136 2-(18-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3] -a][1]benzazepin-5-yljoxy)ethane] NO. oh,

There a) 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]|-5-[2-(tetrahydro-2H-pyran-

266 / 323 2-yloxy)ethoxy]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepine

AND PAN THE

[00731] The title compound was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A] triazolo[4,3-al[1]benzazepin-5-ol (Example 55) and 2-(2-bromoethoxy)tetrahydro-2H-pyran according to the method described in Example 50. MS (ESID) m/ z 539.1 (M+H)*. b 2-(18-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2A]triazolo[4,3-a] [1]benzazepin-5-1l)oxy)ethane]

[00732] A mixture of 146 mg (0.27 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5-[2-(tetrahydro-2H- pyran-2-yloxy)ethoxy]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]|benzazepine (Step a) of Example 136), 4 mL of acetic acid, 2 ml of THF and 1 ml of water was stirred at 45°C for h, then diluted with water. The mixture thus obtained was basified with NaHCO solution; saturated solution, extracted with ethyl acetate, the combined organic layers were dried over MgSO4 , filtered and concentrated to give 118 mg (96%) of the title compound. MS (ESI) m/z 455.4 (M+H)*.

Example 137 (5S)-8-chloro-N N-diethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4 ]triazolo[4,3-a][1]benzazepin-5-amine O.O, fas

No

[00733] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and acetaldehyde according to the method

267 / 323 described in Example 24. MS (EST) m/z 466.4 (M+H)*.

Example 138 8-Chloro-N-methyl-N-(propan-2-yl)-1-[fran-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2,A4|triazolo[4,3-a][1]benzazepin-5-amine o

DS THE

[00734] A mixture of 110 mg (0.24 mmol) of 8-chloro-N-(propan-2-11)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5, 6-dihydro-4H-[1,2A]triazolo[4,3-al[1]benzazepin-5-amine (Example 24), 15 mL methanol, 182 uL 37% solution of formaldehyde in water and 28 µL of acetic acid was cooled to 5°C and 169 mg (0.8 mmol) of sodium triacetoxyborohydride was added to the reaction mixture at such a rate to maintain the internal temperature below 5°C. After the addition was complete the reaction mixture was stirred at room temperature for 24 h, then concentrated. The residue was dissolved in water and the pH adjusted to 8 by the addition of NAHCO solution; saturated solution, then the mixture was extracted with ethyl acetate, the combined organic layers were dried over Na₂SO₄, filtered and concentrated to give 107 g (94%) of the title compound. MS (ESI) m/z 466.2 (M+H)*.

Example 139 [8-Chloro-1-[4-(3-chloropyridin-2-iDpiperazin-1-11]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a ][1]fert-butyl benzazepin-5-ylkcarbamate

THE

[00735] The title compound was prepared from (1-bromo-8-chloro-

268 / 323 tert-Butyl 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1 Ibenzazepin-5-yl)carbamate (Intermediate 94) and 1-(3 -chloropyridin-2-yl)piperazine according to the method described in Example 94. MS (ESI) m/z 530.4 (M+H)*.

Example 140 Ferc 4-(8-chloro-S-methoxy-5,6-dihydro-4H-[1,2,A]triazolo[4,3-all benzazepin-1-yl)piperidine-1-carboxylate -butyl 7, the

[00736] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and 4 tert-butyl -(hydrazinylcarbonylpiperidine-1-carboxylate according to the method described in Example 47. MS (ESI) m/z 433.2 (M+H)* Example 141 N-((5R)-8-chloro -1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1]benzazepin- 5-yl)-D-valinamide

AND

CO cr” a) [OR)-1-(1(5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- tert-Butyl [1,24]triazolo[4,3-a][1]Ibenzazepin-5-yl Yamino)-3-methyl-1-oxobutan-2-ylcarbamate CO , ether and 4

[00737] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-

269/323 a][1]benzazepin-5-amine (Example 8) and cyclobutanecarboxylic acid according to the method described in Step a) of Example 10 and was used without further purification in the next step. b) NHI(SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,24]triazolo[4,3 -a][1]benzazepin-5-1i1)-D-valinamide

[00738] The title compound was prepared from [(2R)-1-(((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6 fert-butyl-dihydro-4H-[1,24]triazolo[4,3-a][1]benzazepin-5-ylJamino)-3-methyl-1-oxobutan-2-ylcarbamate (Step a) of Example 141) according to the method described in Example 6. I7= +7° (c=0.1; methanol); MS (ESI) m/z 509.2 (M+H)*.

Example 142 [1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2,A4]triazole 4,3-a]| 1]benzazepin-5-yl) tert -butyl carbamate a

[00739] A mixture of 552 mg (1.8 mmol) of [2-(methylsulfanyl)-4,5-dihydro-3H-1-benzazepin-4-yl]fert-butyl carbamate (Intermediate 105), 27 mL of 1,4-dioxane, 464 mg (1.97 mmol) of trans-4-(pyridin-2-yloxy)cyclohexanecarbohydrazide (WO 2010/060836 (03.06.2010) F. HOFFMANN-LA ROCHE AG.) and 10 µL of concentrated hydrochloric acid was refluxed under argon for 6.5 h, then concentrated. The residue was purified by column chromatography using dichloromethane : methanol = 95:5 as eluent to give 567 mg (66%) of the title compound. MS (ESID) m/z 476.2 (M+H)*.

Example 143 [8-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a ][1]benzazepin-5-ylkcarbamate of ferc-

270 / 323 butyl O, Cc Or,

LO NHBoc

[00740] The title compound was prepared from tert-butyl [7-fluoro-2-(methylsulfanyl)-4,5-dihydro-3H-1-benzazepin-4-yl]carbamate (Step g) of Intermediate 106) according to the method described in Example 142. MS (ESI) m/z 494.2 (M+H)*. Example 144 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,2,A]triazolo[4,3-a][1]benzazepin- 5-amine cr =

[00741] The title compound was prepared from (1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4 tert-butyl ,3-al[1]benzazepin-5-yl]carbamate (Example 142) according to the method described in Example 6. MS (ESI) m/z 376.2 (M+H)* Example 145 8-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][ 1]benzazepin-5-amine oe

[00742] The title compound was prepared from (8-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2, 4]triazolo[4,3-a][1]benzazepin-5-yl] tert-butyl carbamate (Example 143) according to the method described in Example 6. MS (ESI) m/z 394.2 (M +H)*. Example 146

271 /323 8-Fluoro-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl-5,6-dihydro-4H-1,2,A ]triazolo[4,3-a][1]benzazepin-5-amine Ox,

CO : al

[00743] The title compound was prepared from 8-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4 ]triazolo[4,3-a][1]benzazepin-5-amine (Example 145) according to the method described in Example 24. MS (ESI) m/z 436.2 (M+H)*. Example 147 8-Fluoro-N,N-dimethyl-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-S,6-dihydro-4H-| 1.24 Ythriazolo[4,3-a][1]benzazepin-5-amine F -

[00744] The title compound was prepared from 8-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4 ]triazolo[4,3-a][1]benzazepin-5-amine (Example 145) according to the method described in Example 101. MS (ESI) m/z 436.2 (M+H)*. Example 148 N,N-dimethyl-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo 4,3-a] [1]benzazepin-5-amine

[00745] The title compound was prepared from 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4, 3-al[1]benzazepin-5-amine (Example 144) according to the method described in Example 101. MS (ESI) m/z 404.2 (M+H)*.

Example 149 8'-Fluoro-1'-[trans-4-(trifluoromethyl)cyclohexyl |-4'H,6'H-spiro)| 1,3-dioxolane-2.5"- 1,2,A]triazolo[4,3-a][1]benzazepine 7 Ox

No

[00746] The title compound was prepared from 7-fluoro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolan]-2(3H)-one (Intermediate 92) and trans-4-(trifluoromethyl)cyclohexane carbohydrazide (Intermediate 55) according to the method described in Example 47. MS (ESI) m/z 404.2 (M+H)*.

Example 150 N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4 triazole 4, 3-a][1]benzazepin-5-amine * dO., om

[00747] The title compound was prepared from 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4]triazolo[4, 3-a][1]benzazepin-5-amine (Example 144) according to the method described in Example 24. MS (ESI) m/z 418.2 (M+H)*.

Example 151 N(5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]|-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1]benzazepin-5-yl)tetrahydro-2H-pyran-4-carboxamide

273 /323 . J o DA |

NH

[00748] The title compound was prepared from (5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and tetrahydro-2H-pyran-4-carboxylic acid according to the method described in Step a) of Example 10 [aE=-41° (c=0.1; methanol); MS (ESI) m/z 522.2 (M+H)*. Example 152 N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]| triazolo[4,3-a][1]benzazepin-5-yl)-2-methylbutanamide = N-'/N o IA

NH f MA

[00749] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-al[1]benzazepin-5-amine (Example 7) and 2-methylbutyric acid according to the method described in Step a) of Example 10. MS (ESI) m/z 494 .2 (M+H)*.

[00750] Example 153 N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2, A4]triazolo[4,3-a][1]benzazepin-5-yl)-Nº,Nº-dimethyl-B-alaninamide NO do .

[00751] The title compound was prepared from (55)-8-chloro-1-

274 /323 [trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3-al[1]benzazepin-5- amine (Example 7) and 3-(dimethylamino)propanoic acid according to the method described in Step a) of Example 10. [α]°= -15° (c=0.1; methanol); MS (ESI) m/z 509.2 (M+H)*.

Example 154 (5S)-8-chloro-N-cyclopentyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4] triazolo[4,3-a][1]benzazepin-5-amine

A Ao

[00752] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5S-amine (Example 7) and cyclopentanone according to the method described in Example 24. [- afl=-19º (c=0.1; methanol ); MS (ESI) m/z 478.2 (M+H)*.

Example 155 8'-Chloro-1'-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-yl)-4'H,6'H-spiro[1,3 -dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine

BO or O

[00753] The title compound was prepared from 1'-bromo-8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazole [4,3-a][1]benzazepine] (Intermediate 96) and 3H-spiro[2-benzofuran-1,4'-piperidine] (Combi-Blocks) according to the method described in Example 94. MS (ESI ) m/z 465.2 (M+H)*.

Example 156 8-Chloro-1-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1"-iD)-4H-[1,2,4]triazolo[4,3- a][1]benzazepin-5(6H)-one

275 /323 gives

[00754] The title compound was prepared from 8'-chloro-1"-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1"-11)-4'H, 6'H-spiro[1,3-dioxolane-2,5'-[1,24]triazolo[4,3-a][1]benzazepine] (Example 155) according to the method described in Example 48. MS (ESI) m/z 421.2 (M+H)*.

Example 157 8'-Chloro-1'-[4-(pyridin-2-yloxy)piperidin-1-11]-4'H,6'H-spiro[1,3-dioxolane-2,5'-12, 4 ttriazolo[4,3-a][1]benzazepine

SL à NA os à

[00755] The title compound was prepared from 1'-bromo-8"-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazole [4,3-a][1]benzazepine] (Intermediate 96) and 2-(piperidin-4-yloxy)pyridine according to the method described in Example 94. MS (EST) m/z 454.1 (M+ H)*.

Example 158 N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]|-5,6-dihydro-4H-[1,2,4] triazolo[4,3-a][1]benzazepin-5-yl)-2,2-dimethylbutanamide

SS GIVE. "If

[00756] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and 2,2-dimethylbutyric acid according to the method described in Step a) of Example 10. "= -16° ( c=0.1;

276 / 323 methanol); MS (ESD) m/z 508.2 (M+H)*.

Example 159 N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepin-5-yl)-2-hydroxy-2-methyl propanamide or Ds in

[00757] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-al[1]benzazepin-5-amine (Example 7) and 2-hydroxy-2-methylpropanoic acid according to the method described in Step a) of Example 10. [a]3 "= -30° (c=0.1; methanol); MS (ESI) m/z 496.2 (M+H)*.

Example 160 (5S)-8-chloro-N-ethyl-V-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1, 2,4]triazolo[4,3-a]|[1]benzazepin-5-amine e.g. r

[00758] The title compound was prepared from (55)-8-chloro-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro- 4H-[1,2A]triazolo[4,3-a][1ylbenzazepin-5-amine (Example 78) and acetaldehyde according to the method described in Example 24. [- afl=-37° (c=0, 1; methanol); MS (ESI) m/z 452.2 (M+H)*.

Example 161 (5S)-8-chloro-N-(2-methylpropyl)-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1, 2,A4triazolo[4,3-a][1]benzazepin-5-amine

277 /323 NO...

LO">

[00759] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and isobutyraldehyde according to the method described in Example 24. [- = -22° (c=0.1; methanol) ; MS (ESI) m/z 466.2 (M+H)*. Example 162 8'-Chloro-1'-[trans -4-(morpholin-4-iD)cyclohexyl]-4'H,6'H-spiro) 1,3-dioxolane-2,5'- hydrochloride 1,2,A4]triazolo[4,3-a][1]benzazepine WU. THE

CT O, er 8

[00760] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and trans-4-(morpholin-4-yl)cyclohexane carbohydrazide (Intermediate 81) according to the method described in Example 47. MS (ESI) m/z 445.2 (M+H)* Example 163 8 -chloro-N,N-dimethyl-1-(1'H,3H -spiro[2-benzofuran-1,4"-piperidin]-1'-yl)-5,6-dihydro-4H -[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-amine or -a)[8-chloro-1-(1'H,3H-spiro[2-benzofuran-1 4'- piperidin]-1"'-11)-5,6-dihydro-4H-[1,2A]triazolo[4,3-a][1]benzazepin-5-yl | tert -butyl carbamate

278 /323

[00761] The title compound was prepared from (1-bromo-8-chloro-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1 Ibenzazepin-5 tert-butyl -yl)carbamate (Intermediate 94) and 3H-spiro[2-benzofuran-1 4'-piperidine] (Combi-Blocks) according to the method described in Example 94. MS (ESI) m/z 522 .4 (M+H)*. b) &8-Chloro-1-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1"'-11)-5,6-dihydro-4H-[1,2 Altriazole [4 3-a 1 Ibenzazepin-5-amine

[00762] The title compound was prepared from fert-butyl [8-chloro-1-(1'H,3H-spiro[2-benzofuran-1 4'-piperidin]-1"-11)-5,6 -dihydro-4H-[1,2A]triazolo[4,3-a][1]benzazepin-5-yl]carbamate (Step a) of Example 163) according to the method described in Example 6 and was used without further purification in the next step. c) 8-Chloro-NN-dimethyl-1-(1'H,3H-spiro|[2-benzofuran-1,4'-piperidin]-1"-11)- 5,6 -dihydro-4H-[1,2,4]triazolo[4,3-a][1 Ibenzazepin-5-amine

[00763] The title compound was prepared from 8-chloro-1-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1"'-11)-5,6-di -hydro-4H-[1,2A4]triazolo[4,3-a][1]benzazepin-5-amine (Step b) of Example 163) according to the method described in Example 101. MS (ESI) m /z 450.1 (M+H)*.

Example 164 8'-Chloro-1'-[4-(3-chloropyridin-2-i)piperazin-1-yl]-4'H,6'H-spiro[1,3-dioxolane-2,5'- [1,2,4]triazolo[4,3-a][1]benzazepine

279 / 323 x NO NOs

EB THE

[00764] The title compound was prepared from 1'-bromo-8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazole [4,3-a][1]benzazepine] (Intermediate 96) and 1-(3-chloropyridin-2-yl)piperazine according to the method described in Example 94. MS (ESI) m/z 473.1 ( M+H)*.

Example 165 (5S)-8-chloro-N-(2,2-dimethylpropyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2,A4]triazolo[4,3-a][1]benzazepin-5-amine (O 7 8

[00765] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and trimethylacetaldehyde according to the method described in Example 24. [- = -19° (c=0.1; methanol) ; MS (ESD m/z 522.2 (M+H)*.

Example 166 trans-4-(8-chloro-5-methoxy-5,6-dihydro-4H-1,2,A]triazolo[4,3-a][1]benzazepin-1-yl)cyclo- hexyl |(4-methylpiperazin-1-iDmethanone

TO NA IS

[00766] The title compound was prepared from 7-chloro-4-methoxy-

280 / 323 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and trans-4-[(4-methylpiperazin-1-yl)carbonyl | -hexanecarbohydrazide (Step b) of Intermediate 107) according to the method described in Example 108. MS (ESD m/z 458.3 (M+H)*.

Example 167 (SR)-8-chloro-5-(morpholin-4-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[ 1,2,A4|triazolo[4,3-a][1|benzazepine cÓ Co

[00767] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-al[1]benzazepin-5-amine (Example 8) and bis(2-iodoethyl)ether according to the method described in Example 117. MS (ESI) m/z 480, 2 (M+H)*.

Example 168 N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepin-5-yl Yacetamide MO.

" co , º nl

[00768] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,A]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) according to the method described in Example 9. fr]5 = +29° (c=0.1; methanol) ; MS (ESI) m/z 452.2 (M+H)*.

Example 169 NA(SR)-8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4 ,3-a][1]benzazepin-5-yl)-2-hydroxy-2-methylpropanamide

281 / 323 DF ' 7 DB

[00769] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and 2-hydroxy-2-methylpropanoic acid according to the method described in Step a) of Example 10. [a] 3°= +32° (c=0.1; methanol); MS (ESI) m/z 496.2 (M+H)*. Example 170 8-Chloro-S-methoxy-1-[1-(tetrahydro-2H-pyran-4-yl)piperidin-4-11]-5,6-dihydro-4H-[1,2, 4]triazolo[4,3-a][1]benzazepine O.

the and the

[00770] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and 1 -(Tetrahydro-2H-pyran-4-yl)piperidine-4-carbohydrazide (Intermediate 108) according to the method described in Example 108. MS (ESD) m/z 417.2 (M+H)*. Example 171 8'-Chloro-1'-[4-(pyridin-2-yl)piperazin-1-yl]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1] ,2,4]triazolo[4,3-a][1]benzazepine

GC NO NO) >

[00771] The title compound was prepared from 1'-bromo-8"-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazole [4,3-a][1]benzazepine]

282/323 (Intermediate 96) and 1-(pyridin-2-yl)piperazine according to the method described in Example 94. MS (EST) m/z 439.2 (M+H)*.

Example 172 8-Chloro-1-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1'-i)-5,6-dihydro-4H-[1,2, A4]triazolo[4,3-a][1]benzazepin-5-ol

oh oh

[00772] The title compound was prepared from 8-chloro-1-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1"-11)-4H-[1,2 ,4]triazolo[4,3-a][1]benzazepin-5(6H)-one (Example 156) according to the method described in Example 49. MS (ESI) m/z 423.2 (M+H )*.

Example 173 8-Chloro-1-[4-(3-chloropyridin-2-i)piperidin-1-yl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3- a][1]benzazepin-5-ol "oa) &8-chloro1-[4-(3-chloropyridin-2-yl)piperidin-1-11)-4H-[1,24]triazolo — [4,3 - al[1 Ibenzazepin-5(6H)-one o

[00773] The title compound was prepared from 8'-chloro-1"-[4-(3-chloropyridin-2-yl)piperazin-1-11])-4'H,6'H-spiro[1 ,3-dioxolane-2,5'"-[1,2 A]triazolo[4,3-a][1]benzazepine] (Example 164) according to the method described in Example 48. MS (EST) m/ z 429.0 (M+H)*. b 8-chloro-1-[4-(3-chloropyridin-2-yl)piperidin-1-11]1-5,6-dihydro-4H-[1,2,4

283 / 323 triazolo[4,3-a][1]benzazepin-5-ol

[00774] The title compound was prepared from 8-chloro-1-[4-(3-chloropyridin-2-yl)piperidin-1-11]-4H-[1,2,4]triazolo[4,3 -a][1]benzazepin-5(6H)-one (Step a) of Example 173) according to the method described in Example 49. MS (ESID) m/z 431.1 (M+H)*.

Example 174 (SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5-(pyrrolidin-1-i)-5,6-dihydro-4H-[ 1,2,4]triazolo[4,3-a]|[1]benzazepine Cr O : Is it?

LO THE

[00775] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and 1,4-dibromobutane according to the method described in Example 117. MS (ESI) m/z 464.2 (M+H)*.

Example 175 8-Chloro-S-methoxy-1-[1-[(3S)-tetrahydrofuran-3-ylpiperidin-4-111-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1]benzazepine; du,

[00776] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and 1 -[(3S)-tetrahydrofuran-3-yl piperidine-4-carbohydrazide — (Step b) of Intermediate 109) according to the method described in Example 108. MS (ESID) m/z 403.2 (M+H) *.

Example 176 (SR)-8-fluoro-S-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclo-

284 / 323 hexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine

CS 7 DB and Example 177 (5S)-8-fluoro-5-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1, 2,4]triazolo[4,3-a][1]benzazepine

DOF and

[00777] The title compounds were obtained from 8-fluoro-5-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 4]triazolo[4,3-a][1 Racemic Ibenzazepine (Example 134) by chiral preparative HPLC (CHIRALPAK IG 20 µm preparative stationary phase; 5x30cm; F=50mL/min; eluent: tert-butyl methyl ether : dichloromethane : ethanol = 92:3:5; isocratic; t=25°C). Optical rotation of the first compound eluting (T, 17.3 min) was [&fan= -7° (c=0.1; methanol); and that of the second eluting compound (T, 21.7 min) was fam? = +12° (c=0.1; methanol). The absolute configuration of the compounds has not been determined.

Example 178 8-Chloro-S5-methoxy-1-([1-[(3R)-tetrahydrofuran-3-ylpiperidin-4-1137-5,6-dihydro-4H-[1,2,4]triazole [4,3-a][1]benzazepine =.

[00778] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and 1 -[R)-tetrahydrofuran-3-yl |piperidine-4-carbohydrazide — (Step b) of

285 / 323 Intermediate 110) according to the method described in Example 108. MS (ESD m/z 403.2 (M+H)*.

Example 179 N(SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4 ,3-a][1]benzazepin-5-yl)-Nº,Nº-dimethyl-B-alaninamide xoo

[00779] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-al[1]benzazepin-5-amine (Example 8) and 3-(dimethylamino)propanoic acid according to the method described in Step a) of Example 10. [a]s" = +20° (c=0.1; methanol); MS (ESI) m/z 509.2 (M+H)*.

Example 180 N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4|triazole [4,3-a][1]benzazepin-5-yl)tetrahydro-2H-pyran-4-carboxamide Cc A 2N er , SS

[00780] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5S-amine (Example 8) and tetrahydro-2H-pyran-4-carboxylic acid according to the method described in Step a) of Example 10 [aEo=+29° (c=0.1; methanol); MS (ESI) m/z 522.2 (M+H)*.

Example 181

286 / 323 8-chloro-1-[4-(pyridin-2-yloxy)piperidin-1-yl]-5,6-dihydro-4H-1,2,A]triazolo[4,3-a] [1]benzazepin-5-ol

SRS

[00781] º or a) 8-chloro-1-[4-(pyridin-2-yloxy)piperidin-1-11]-4H-[1,2,A4]triazolo[4,3-a][1 benzazepin -5(6H)-one

CC O Ay,

LX or

[00782] The title compound was prepared from 8'-chloro-1"-[4-(pyridin-2-yloxy)piperidin-1-11])-4'H,6'H-spiro[1,3 -dioxolane-2,5'-[1,24]triazolo[4,3-a][1Ibenzazepine] (Example 157) according to the method described in Example 48 and was used without further purification in the next step. 8-Chloro-1-[4-(3-chloropyridin-2-yl)piperidin-1-111-5,6-dihydro-4H-[1,2,4-triazolo[4,3-a][1 Ibenzazepin-5-ol

[00783] The title compound was prepared from 8-chloro-1-[4-(3-chloropyridin-2-yl)piperidin-1-11]-4H-[1,2,A4]triazolo[4,3 -a][1]|benzazepin-5(6H)-one (Step a) of Example 181) according to the method described in Example 49. MS (ESI) m/z 412.2 (M+H)*. Example 182 8-Chloro-S-methoxy-1-[trans-4-(4-methylpiperazin-1-iDcyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1]benzazepine Po . Õ

LO and Example 183 8-Chloro-S-methoxy-1-[cis-4-(4-methylpiperazin-1-yl)cyclohexyl]-

287 /323 5,6-dihydro-4H-1,2,4 Ythriazolo[4,3-a][1]benzazepine A. The b

LQ

[00784] The title compounds were prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and a mixture of cis-4-(4-methylpiperazin-1-yl)cyclohexanecarbohydrazide (Intermediate 113) and trans-4-(4-methylpiperazin-1-yl)cyclohexane carbohydrazide (Intermediate 114) according to the described method in Example 108. The cis- and trans isomers were separated by preparative HPLC (Lux Amylose with 1.5um stationary phase; 150x21.2 mm; F = 22mL/min; eluent: A: water+0.1% TFA, B: acetonitrile+0.1% TFA, gradient: B% 10 — 90; t=40°C) According to 'NMR spectroscopy, the first fraction (retention time: 6.6 min) was 8-chloro-S-methoxy- 1-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1]benzazepine (Example 182), while the second fraction (retention time: 8.6 min) was 8-chloro-5-methoxy-1-[cis-4-(4-methylpiperazin-1-yl)cyclohexyl]-5 ,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]|benzazepine (Example the 183). MS (ESD m/z 430.2 (M+H)*.

Example 184 8-Chloro-S-methoxy-1-[1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1]benzazepine N " ci o

[00785] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and 1 -(pyridin-3-ylmethyl)pyrrolidine-3-carbohydrazide (Step b) of Intermediate 115) according to the method described in Example 108. MS (ESI) m/z 410.2

288 / 323 (M+H)*.

Example 185 8-Chloro-S5-methoxy-1-[1-(pyridin-2-ylmethyl)pyrrolidin-3-yl]-5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1]benzazepine” 2X chromo-

[00786] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and 1 -(pyridin-2-ylmethyl)pyrrolidine-3-carbohydrazide (Step b) of Intermediate 116) according to the method described in Example 108. MS (ESI) m/z 410.2 (M+H)*.

Example 186 N-Á(SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4-triazolo 4 ,3-a][1]benzazepin-5-yl)-2-cyanoacetamide c6

[00787] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and cyanoacetic acid according to the method described in Step a) of Example 10. [a]3º= +32º (c =0.1; methanol); MS (ESD m/z 477.3 (M+H)*.

Example 187 3-(8-Chloro-5-methoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-al[1]benzazein-1yl irrolidin-1-yl( pyridin-3-ylmethanone cr o

289 / 323

[00788] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and 1 -(pyridin-3-ylcarbonyl)pyrrolidine-3-carbohydrazide (Step b) of Intermediate 117) according to the method described in Example 108. MS (ESI) m/z 424.2 (M+H)*.

Example 188 8'-Chloro-1'-[1-[(3R)-tetrahydrofuran-3-yl piperidin-4-yl)-4'H,6'H-spiro[1,3-dioxolane-2.5" - 1,2,A]triazolo[4,3-a][1]benzazepine O.o.

AN AT

[00789] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and 1-[GR)-tetrahydrofuran-3-yl]piperidine-4-carbohydrazide — (Step b) of Intermediate 110) according to the method described in Example 108. MS (ESD m/z 431.2 (M+H )*.

Example 189 3-(8-Chloro-5-methoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-iDpyrrolidin-1-yl )(pyridin-2-iDmethanone and the

[00790] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and 1 -(pyridin-2-ylcarbonyl)pyrrolidine-3-carbohydrazide (Step d) of Intermediate 118) according to the method described in Example 108. MS (ESI) m/z 424.2 (M+H)*.

Example 190

290 / 323 trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-1,2,A]triazolo[4,3-a][1 ]benzazepin]-1'-iD)-NV,N-dimethylcyclohexanamine

OA S Do

[00791] Under argon to a mixture of 100 mg (0.69 mmol) of 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolan]-2(3H )-one (Intermediate 53), 10 mL of dichloromethane and 218 mg (1.58 mmol) of K2CO; 117 mg (0.788 mmol) of trimethyloxonium tetrafluoroborate was added. The reaction mixture was stirred at room temperature for 20 h, then filtered. The filtrate was concentrated and the residue was dissolved in 20 ml of acetonitrile. 39 µL (0.51 mmol) of trifluoroacetic acid and 87.6 mg (0.47 mmol) of trans-4-(dimethylamino)cyclohexanecarbohydrazide — (Intermediate = 80) were added and the reaction mixture was stirred at 70°C for 3 hrs. After concentration, the residue was dissolved in dichloromethane and washed with 5% HCl solution. The organic phase was discarded. The pH of the acidic water phase was adjusted to 8 by adding NaCO solution; saturated and extracted with dichloromethane. The combined organic layers were dried over MgSO4 , filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane:methanol:ammonium hydroxide = 180:10:1 solution as eluent to give 56 mg (35%) of the title compound. MS (ESD) m/z 403.2 (M+H)*.

Example 191 8-Chloro-S-methoxy-1-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin-1"-iN)-5,6-dihydro-4H-1, 2,A]triazolo[4,3-a][1]benzazepine

LO

[00792] The title compound was prepared from 8-chloro-1-(1'H,3H-spiro[2-benzofuran-1,4'-piperidin]-1"-yl)-5,6-di- hydro-4H-[1,2A]triazolo[4,3-

291 /323 a][1]benzazepin-5-ol (Example 172) according to the method described in Example 50. MS (ESD m/z 437.2 (M+H)*.

Example 192 8-Chloro-1-[4-(3-chloropyridin-2-i))piperazin-1-yl]-S-methoxy-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepine

[00793] The title compound was prepared from 8-chloro-1-[4-(3-chloropyridin-2-yl)piperidin-1-11]-5,6-dihydro-4H-[1,2 ,A4]triazolo[4,3-al[1]benzazepin-5-ol (Example 173) according to the method described in Example 50. MS (ESI) m/z 445.2 (M+H)*.

Example 193 N-1trans -4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-1,2,A]triazolo[4,3-ao benzazepin] -1'-iDcyclohexylpyridin-2-amine AS,

[00794] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and trans-4-(pyridin-2-ylamino)cyclohexane-carbohydrazide — (Step b) of Intermediate 135) according to the method described in Example 190. MS (ESD m/2 452.2 (M+H) *.

Example 194 N'-(SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepin-5-yl+-N,N-dimethylethane-1,2-diamine

292 / 323 To the TFT U,, LO. x

[00795] A mixture of 100 mg (0.24 mmol) of (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro- 4H-[1,2,A4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8), 15 mL ethanol, 14 uL (0.24 mmol) acetic acid, 30 mg ( 0.4 mmol) of 2-(dimethylamino)acetaldehyde hydrochloride and 46 mg (0.73 mmol) of sodium cyanoborohydride was stirred at room temperature for 20 h, then concentrated. The residue was dissolved in NaHCO solution; saturated and extracted with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane:methanol:ammonium hydroxide = 95:5:0.1 solution as eluent to give 39 mg (33%) of the title compound. MS (ESD m/z 481.3 (M+H)*.

Example 195 S$-Chloro-1-[frans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3] acetate -a][1]benzazepin-5-yl NO. Oh,

NO,

[00796] A mixture of 100 mg (0.24 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1] ,2 4]triazolo[4,3-al[1]benzazepin-5-ol (Example 55), 10 mL of dichloromethane, 23 uL (0.24 mmol) of acetic anhydride and 34 uL (0.24 mmol) of TEA was stirred at room temperature for 24 h, then 23 ul (0.24 mmol) of acetic anhydride and 34 ul (0.24 mmol) of TEA were added and stirring was continued at room temperature for a further 24 h. Then 23 uL (0.24 mmol) of acetic anhydride and 34 uL (0.24 mmol) of TEA were added and

Stirring was continued at room temperature for a further 24 h. The mixture was concentrated and purified by flash column chromatography using dichloromethane:methanol:ammonium hydroxide=9:1:0.1 solution as eluent to give 47 mg (43%) of the title compound. MS (ESI) m/z 453.2 (M+H)*.

Example 196 2-(1(5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,24-triazole 4,3 -a][1]benzazepin-5-yl Yamino)ethanol

S PO,

CO ' No a) (5R)-N-[2-(benzyloxy)ethyl]-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro -4H- 1 2 4 ttriazolo[4,3-a][1 Ibenzazepin-5-amine SO,

THE TO THE

[00797] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and benzyloxyacetaldehyde according to the method described in Example 194. MS (ESI) m/z 544.3 (M+H )*. b) 2-(1(5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-1,24]triazolo[ 4,3-a][1 Ibenzazepin-5-11)amino)ethanol

[00798] A mixture of 144 mg (0.26 mmol) of (SR)-N-[2-(benzyloxy)ethyl]-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclo- hexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1|benzazepin-5-amine (Step a) of Example 196) and mL of 6N HCl solution was refluxed for 1 h, then cooled to room temperature and the pH of the mixture was adjusted to 7 by addition of NaxCO solution; saturated. The mixture thus obtained was extracted with ethyl acetate,

the combined organic layers were dried over Na7SO4, filtered and concentrated. The residue was crystallized with chloroform to give 53 mg (44%) of the title compound. The mother liquor was purified by flash column chromatography using dichloromethane:methanol = 95:5 as eluent to give 59 mg (49%) of the title compound. MS (ESI) m/z 454.2 (M+H)*.

Example 197 8-Chloro-S-methoxy-1-[4-(pyridin-2-yloxy)piperidin-1-yl]-5,6-dihydro-4H-[1,2,4-triazolo) 4,3 -a][1]benzazepine

CO | Mr

[00799] The title compound was prepared from 8-chloro-1-[4-(3-chloropyridin-2-yl)piperidin-1-11]-5,6-dihydro-4H-[1,2 ,A]triazolo[4,3-al[1]benzazepin-5-ol (Example 181) according to the method described in Example 50. MS (ESD) m/z 426.2 (M+H)*.

Example 198 8'-Chloro-1'-(tfrans-4-methoxy-4-methylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2, 4]triazolo[4,3-a][1]benzazepine Po,

[00800] Under argon to a mixture of 100 mg (0.39 mmol) of 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolan]-2(3H )-one (Intermediate 53) and 10 mL of dichloromethane 3 uL (0.04 mmol) of trifluoroacetic acid and 70 mg (0.47 mmol) of trimethyloxonium tetrafluoroborate were added. The reaction mixture was stirred at room temperature for 20 h, then 147 mg (0.79 mmol) of a 21:79 mixture of cis-4-methoxy-4-methylcyclohexanecarbohydrazide and trans-4-methoxy-4-methylcyclo -hexane carbohydrazide

295 / 323 (Intermediate 119) were added and the reaction mixture was refluxed for 8 h. After concentration, the residue was dissolved in 20 mL of 1,4-dioxane and the mixture was refluxed for 6 h, then concentrated. The residue was purified by flash column chromatography using dichloromethane:methanol:ammonium hydroxide = 180:10:1 solution as eluent to give 82 mg (52%) of the title compound. MS (ESI) m/z 404.1 (M+H)*.

Example 199 (5S)-8-chloro-N-(cyclopropylmethyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2, A4|triazolo[4,3-a][1]benzazepin-5-amine cr">

[00801] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and cyclopropanecarboxaldehyde according to the method described in Example 24. "= -28° (c=0.1; methanol); MS (ESD m/z 464.2 (M+H)*.

Example 200 N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]| triazolo[4,3-a][1]benzazepin-5-yl)-1-methylpiperidine-4-carboxamide or Ds NO.

Q

[00802] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-

a][1]benzazepin-5-amine (Example 7) and 1-methylpiperidine 4-carboxylic acid according to the method described in Step a) of Example 10. [a]ãº= -31º (c=0 .1; methanol); MS (ESI) m/z 535.5 (M+H)*.

Example 201 N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl |-5,6-dihydro-4H-[1,2,4]| triazolo[4,3-a][1]benzazepin-5-yl)-2,2,2-trifluoroacetamide e.g.

THE,

[00803] A mixture of 82 mg (0.2 mmol) of (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro- 4H-[1,2,A4]triazolo[4,3-a][1]benzazepin-5-amine (Example 7), 5 mL of dichloromethane, 73 uL (0.4 mmol) of DIPEA and 55 uL (0 .4 mmol) of trifluoroacetic anhydride was stirred at room temperature for 20 h, then 73 ul (0.4 mmol) of DIPEA and 55 ul (0.4 mmol) of trifluoroacetic anhydride were added and stirring was continued for 3 h. The mixture was diluted with dichloromethane, washed with NaHCO solution; saturated solution, dried over NaSO4 , filtered and concentrated to give 100 mg (99%) of the title compound. 1687= -13° (c=0.1; methanol); MS (ESI) m/z 506.2 (M+H)*.

Example 202 8-Chloro-5-(2-methoxyethoxy)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl-5,6-dihydro-4H-1,2,4]triazolo[ 4,3-a][1]benzazepine 2

LO x

[00804] The title compound was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24] triazole[4,3-

297 / 323 a][1]benzazepin-5-ol (Example 55) and 2-bromoethyl methyl ether according to the method described in Example 50. MS (ESI) m/z 469.4 (M+H)* . Example 203 8-Chloro-1-(4-methoxy-4-methylcyclohexyl)-N-(propan-2-yl)-5,6-dihydro-447-[1,2,4]triazolo[4] ,3-a][1]benzazepin-S-amine o = a) 8-chloro-1-(4-methoxy-4-methylcyclohexyl)-5,6-dihydro-4H-[1,24 ]triazolo 4,3-a][1 Ibenzazepin-5-yl |tert-butyl carbamate /

FP

[00805] The title compound was prepared from tert-butyl (7-chloro-2-thioxo-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate (Intermediate 4 ) and a 21:79 mixture of cis-4-methoxy-4-methylcyclohexanecarbohydrazide and trans-4-methoxy-4-methylcyclohexane carbohydrazide (Intermediate 119) according to the method described in Example 1. MS (ESD) m/z 461.4 (M+H)*. b 8-chloro-1-(4-methoxy-4-methylcyclohexyl)-5,6-dihydro-4H-[1,24]triazolo 4,3-a][1|benzazepin-5-amine at 2

LO

[00806] The title compound was prepared from [8-chloro-1-(4-methoxy-4-methylcyclohexyl)-5,6-dihydro-4H-[1,2,A]triazolo[4 tert-Butyl ,3-al[1]benzazepin-5-yl]carbamate (Step a) of Example 203) according to the method described in Example 2 and was used without further

298 / 323 purification in the next step. c) B8-chloro-1-(A-methoxy-4-methylcyclohexyl)-N-(propan-2-yl)-5,6-dihydro-4H-1,2A]triazolo[4,3 -a][1]benzazepin-5-amine

[00807] The title compound was prepared from 8-chloro-1-(4-methoxy-4-methylcyclohexyl)-5,6-dihydro-4H-[1,24]triazolo[4,3 - a][1]benzazepin-5-amine (Step b) of Example 203) according to the method described in Example 24, it was an 8:92 mixture of cis- and trans-isomers. MS (ESD m/z 403.2 (M+H)*. Example 204 8'-Chloro-1'-(trans-4-methoxy-4-methylcyclohexyl)-4'H,6'H-spiro[ 1,3-dioxane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine o.

OD and Example 205 8'-Chloro-1'-(cis-4-methoxy-4-methylcyclohexyl)-4'H,6'H-spiro[1,3-dioxane-2,5'-[1, 2,4]triazolo[4,3-a][1]benzazepine e, NX NXIA À ;

DO

[00808] The title compounds were prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxan]-2(3H)-one — (Intermediate 98 ) and a 21:79 mixture of cis-4-methoxy-4-methylcyclohexanecarbohydrazide and trans-4-methoxy-4-methylcyclohexanecarbohydrazide (Intermediate 119) according to the method described in Example 198. The cis- and trans- were separated by flash column chromatography using dichloromethane:methanol:ammonium hydroxide = 180:10:1 solution as eluent. According to "NMR spectroscopy, the first fraction was 8'-chloro-1'"-

299 / 323 (trans-4-methoxy-4-methylcyclohexyl)-4'H,6'H-spiro[1,3-dioxane-2,5'-[1,24]triazolo[4,3- a][1 Ibenzazepine] (Example 204), while the second fraction was &8'-chloro-1'-(cis-4-methoxy-4-methylcyclohexyl)-4'H,6'H-spiro[1, 3-dioxane-2,5'-[1,2,4]triazolo[4,3-a][1]/benzazepine] (Example 205). MS (ESD m/z 418.2 (M+H)*.

Example 206 8-Chloro-5-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1]benzazepine o.

[00809] Under argon, a stirred solution of 170 mg (0.41 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro- 4H-[1,24]triazolo[4,3-a][1]benzazepin-5-ol (Example 55) in 10 mL of dichloromethane was cooled to -78°C and a solution of 147 mg (0.91 mmol) of (diethylamino)sulfur trifluoride in 5 ml of dichloromethane was added. The reaction mixture was allowed to warm to room temperature over 5 h, then diluted with NaHCO solution; saturated, the phases were separated and the water phase was extracted with dichloromethane. The combined organic phases were dried over MgSO4 , filtered and concentrated. The residue was purified by reverse phase flash column chromatography using acetonitrile and 0.1% TFA containing water = 35:65 as eluent to give 15 mg (9%) of the title compound. MS (ESI) m/z 413.1 (M+H)*.

Example 207 8-Chloro-5-[2-(methylsulfonyDethoxy]-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4 ]triazolo[4,3-a][1]benzazepine

300 / 323 No. “Oy, Le n o

[00810] The title compound was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4] triazolo[4,3-al[1]benzazepin-5-ol (Example 55) and 1-bromo-2-(methylsulfonyl)ethane according to the method described in Example 50. MS (ESI) m/z 517.1 (M+H)*.

Example 208 8-Chloro-N-hydroxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4H-[1,2,4-triazolo 4,3-a 1]benzazepin-5(6H )-imine OO,

[00811] A mixture of 100 mg (0.245 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4H-[1,24]triazolo[4,3- a][1]benzazepin-5(6H)-one (Example 54), 5 mL of pyridine, 5 mL of methanol and 17 mg (0.245 mmol) of hydroxylamine hydrochloride was refluxed for 3 h, then concentrated. The residue was dissolved in dichloromethane, washed with 5% citric acid solution and water, the organic phase was dried over MgSO4 , filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane:methanol:ammonium hydroxide = 180:10:1 solution as eluent to give 34 mg (33%) of the title compound. MS (EST) m/z 424.1 (M+H)*.

Example 209 (SS)-8-chloro-N-methyl-N-(prop-2-yn-1-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6 -dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine

301/323

THE RX

[00812] A mixture of 43 mg (0.1 mmol) of (55)-8-chloro-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6- dihydro-4H-[1,2A]triazolo[4,3-a][1]benzazepin-5-amine (Example 78), 5 mL acetone, 20 uL (0.13 mmol) 80°C solution % propargyl bromide in toluene and 42 mg (0.13 mmol) of cesium carbonate was stirred at room temperature for 20 h, then 20 uL (0.13 mmol) of 80% solution of propargyl bromide in toluene and 42 mg (0.13 mmol) of cesium carbonate was added and stirring was continued for 20 h. The reaction mixture was filtered, the filtrate was concentrated and the residue was purified by column chromatography using dichloromethane:methanol = 9:1 as eluent to give 30 mg (64%) of the title compound. [&T"=-22° (c=0.1; methanol); MS (ESI) m/z 462.1 (M+H)*.

Example 210 N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo [4,3-a][1]benzazepin-5-yl)-3,3-difluorocyclobutane carboxamide <a

[00813] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-al[1]benzazepin-5-amine (Example 7) and 3,3-difluorocyclobutanecarboxylic acid according to the method described in Step a) of Example 10. [a]3°=- 37° (c=0.1; methanol); MS (ESI) m/z 528.2 (M+H)*.

Example 211 8-Chloro-5-(prop-2-yn-1-yloxy)-1-[trans-4-(pyridin-2-

302/323 yloxy)cyclohexyl-5,6-dihydro-4H-1,2,A]triazolo[4,3-a][1]benzazepine cc ]

[00814] The title compound was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24] triazolo[4,3-al[1]benzazepin-5-ol (Example 55) and 80% solution of propargyl bromide in toluene according to the method described in Example 50. MS (ESI) m/z 449.2 (M+H)*.

Example 212 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a] [1]benzazepin-5-yl. — 4,4-difluorocyclo — hexane carboxylate s

TOA

[00815] Under argon, a mixture of 80 mg (0.19 mmol) of 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H -[1,2 A]triazolo[4,3-a][1]benzazepin-5-ol (Example 55), 15 mL of dichloromethane, 35 mg (0.21 mmol) of 4,4-difluorocyclohexanecarboxylic acid 44 mg (0.21 mmol) of N,N'-dicyclohexylcarbodiimide and 24 mg (002 mmol) of 4(dimethylamino)pyridine were stirred at room temperature for 20 h. After completing the reaction, the mixture was diluted with water, 10% NaHCO solution; and dichloromethane. The phases were separated, the organic phase was dried over MgSO4 , filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane:methanol=95:5 as eluent to give 66 mg (61%) of the title compound. MS (ESI) m/z 557.2

303 / 323 (M+H)*.

Example 213 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazole 3,3-difluorocyclobutane carboxylate 4,3-a][1 benzazepin-5-ila

[00816] The title compound was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4] triazolo[4,3-al[1]benzazepin-5-ol (Example 55) and 3,3-difluorocyclobutane carboxylic acid according to the method described in Example 212. MS (ESI) m/z 529.2 (M+ H)*.

Example 214 N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepin-5-yl)-4,4-difluorocyclohexanecarboxamide

THE

EN Fr

[00817] The title compound was prepared from (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,A]triazolo[4,3-a][1]benzazepin-5-amine — (Example 7) and 4,4-difluorocyclohexanecarboxylic acid according to the method described in Step a) of Example

10. [α]ã=-34° (c=0.1; methanol); MS (ESI) m/z 556.2 (M+H)*.

Example 215 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a] [1]benzazepin-5-yl cyanoacetate

304 / 323 NO», N 7 Ace

[00818] The title compound was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24] triazolo[4,3-a][1]benzazepin-5-ol (Example 55) and cyanoacetic acid according to the method described in Example 212. MS (ESI) m/z 478.1 (M+H)*. Example 216 8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a] [1]benzazepin-5-yl N,NV-dimethylglycinate TX O.o A

No

[00819] The title compound was prepared from 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4] triazolo[4,3-al[1]benzazepin-5-ol (Example 55) and N,N-dimethylglycine according to the method described in Example 212. MS (ESI) m/z 496.2 (M+H) *. Example 217 N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazole [4,3-a][1]benzazepin-5-yl)-2,2,2-trifluoro acetamide CC'" E er Se do.

[00820] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) according to the method described in Example 201. [a]3°= +21° (c=0.1; methanol ); MS (ESI) m/z 506.1 (M+H)*. Example 218

305 / 323 1-[cis-4-(8-chloro-S-methoxy-5,6-dihydro-4H-1,2,A]triazolo) and 1]benzazepin-1-iDcyclohexyl]pyrrolidin-2 -one J [2

THE

[00821] and Example 219 1-[trans-4-(8-chloro-S-methoxy-5,6-dihydro-4H-1,2A]triazolo[4,3-a][1]benzazepin- 1-iDcyclohexyl pyrrolidin-2-one Fr

[00822] The title compounds were prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and 4 -(2-oxopyrrolidin-1-yl)cyclohexanecarbohydrazide (Intermediate 120) according to the method described in Example 108. The cis- and trans isomers were separated by preparative HPLC (Kinetex EVO CI18 with Sum stationary phase; 150x21, 2 mm; F = 20mL/min; eluent: A: water+0.1% TFA, B: acetonitrile+0.1% TFA, gradient: B% 0.6 — 35; t=40ºC) According to spectroscopy of 'NMR the first fraction (retention time: 18.5 min) was 1-[cis4-(8-chloro-5S-methoxy-5,6-dihydro-4H-[1,2,4]triazolo[4] ,3-a][1]benzazepin-1-yl)cyclohexyl]pyrrolidin-2-one (Example 218), while the second fraction (retention time: 19.2 min) was 1-[trans-4- (8-chloro-5-methoxy-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1Ibenzazepin-1-yl)cyclohexyl]pyrrolidin-2-one (Example 219). MS (ESI) m/z 415.2 (M+H)*. Example 220 N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl 1-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepin-5-yl)-3,3-difluorocyclo

306 / 323 butanecarboxamide or Ned

SIS 7 "o d PO

[00823] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and 3,3-difluorocyclobutanecarboxylic acid according to the method described in Step a) of Example 10. [4]s= +48° (c=0.1; methanol); MS (ESI) m/z 528.2 (M+H)*. Example 221 N-Á(SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazole [4,3-a][1]benzazepin-5-yl)-4,4-difluorocyclohexanecarboxamide Non FO: gives the F

F

[00824] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-S-amine — (Example 8) and 44-difluorocyclohexanecarboxylic acid according to the method described in Step a) of Example

10. [a]R°=+38° (c=0.1; methanol); MS (ESI) m/z 556.2 (M+H)". Example 222 8-Chloro-S-methoxy-1-[cis-4-methoxy-4-(trifluoromethyl)º-cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4] ,3-a][1]benzazepine to

[00825] The title compound was prepared from 7-chloro-4-methoxy-

307 / 323 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and cis-4-methoxy-4-(trifluoromethyl)cyclohexanecarbohydrazide (Intermediate 123 ) according to the method described in Example 108. MS (ESI) m/z 430.2 (M+H)*.

Example 223 8-Chloro-S-methoxy-1-[trans-4-methoxy-4-(trifluoromethyl)cyclohexyl-5,6-dihydro-4H7-1,2,A4]triazolo[4,3- a][1]benzazepine

FX ro,

LO

[00826] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and trans -4-methoxy-4-(trifluoromethyl)cyclohexanecarbohydrazide — (Intermediate 124) according to the method described in Example 108. MS (ESI) m/z 430.2 (M+H)*.

Example 224 (SS)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]|-N-(2,2,2-trifluoroethyl)-5,6-dihydro- 4H-[1,2,A]triazolo[4,3-a][1 benzazepin-S-amine

CO

[00827] A mixture of 82 mg (0.2 mmol) of (55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro- 4H-[1,24]triazolo[4,3-al[1]benzazepin-5-amine (Example 7), 10 mL dichloromethane, 190 uL (1.32 mmol) 2,2,2-trifluoromethanesulfonate trifluoroethyl and 230 uL (1.32 mmol) of DIPEA was stirred at room temperature for 20 h, then 190 uL (1.32 mmol) of 2,2,2-trifluoroethyl trifluoromethanesulfonate and 230 uL (1.32 mmol) of DIPEA were added and stirring was continued

308 / 323 at 40°C for 90 h. The reaction mixture was concentrated and water was added to the residue. The solid precipitated material was filtered, washed with water and purified by column chromatography using dichloromethane:methanol = 9:1 as eluent to give 8 mg (8%) of the title compound. MS (ESI) m/z 492.2 (M+H)*.

Example 225 N(5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl |-5,6-dihydro-4H-[1,2,4]triazolo[4] ,3-a][1]benzazepin-5-yl)-3-methyloxetane-3-carboxamide (Oy, L6 of

[00828] The title compound was prepared from (5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 7) and 3-methyloxetane-3-carboxylic acid according to the method described in Step a) of Example 10. [a] s°= -28° (c=0.1; methanol); MS (ESI) m/z 508.3 (M+H)*.

Example 226 N-(SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1]benzazepin-5-yl-3-methyloxetane-3-carboxamide ( 7 DB o 2 do

[00829] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-amine (Example 8) and 3-methyloxetane-3-carboxylic acid according to the method described in Step a) of Example 10. [a] ã'=+26th

309 / 323 (c=0.1; methanol); MS (ESI) m/z 508.2 (M+H)*.

Example 227 trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-1,2,A]triazolo[4,3-a][1] benzazepin]-1'-II)-N-(4-methoxybenzyl)cyclohexanamine or neo Ox,

[00830] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and trans-4-[(4-methoxybenzyl)amino]-cyclohexanecarbohydrazide (Intermediate 125) according to the method described in Example 108. MS (ESI) m/z 495.2 (M+H)*.

Example 228 2-(1(5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]|-5,6-dihydro-4H-[1,2,4 ]triazolo[4,3-a][1]benzazepin-5-ylamino)ethyl]ferc-butyl carbamate FO:

CO 'IN 800

[00831] The title compound was prepared from (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]ltriazolo[4,3-a][1]benzazepin-5-amine (Example 8) and tert-butyl (2-oxoethyl)carbamate according to the method described in Example 190. MS (ESI) m/ z 432.2 (M+H)*.

Example 229 8'-Chloro-1'-(trans-4-ethoxy-4-ethylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2, 4]triazolo[4,3-a][1]benzazepine

? oh so

[00832] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and trans-4-ethoxy-4-ethylcyclohexane-carbohydrazide (Step c) of Intermediate 126) according to the method described in Example 190. MS (ESI) m/z 432.2 (M+H)*.

Example 230 trans -4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-1,2,A]triazolo[4,3-a][1] benzazepin]-1'-yl)-V-(4-methoxybenzyl)-N-methylcyclohexanamine o. à O Na is ?

[00833] The title compound was prepared from trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5"-[1,2,4]triazole [4,3-a][1]benzazepin])-1"-yl)-N-(4-methoxybenzyl)-cyclohexanamine (Example 227) according to the method described in Example 101. MS (ESI) m /z 509.2 (M+H)*.

Example 231 8'-Chloro-1'-[1-(pyridin-3-ylmethyl)pyrrolidin-3-11]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1] ,2,4]triazolo[4,3-a][1]benzazepine

DSO O, ONLY

[00834] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and 1-(pyridin-3-ylmethyl)pyrrolidine-3-carbohydrazide (Step b) of Intermediate 115) according to the method described in Example 108. MS (ESI) m/z 438.2

(M+H)*.

Example 232 8-Chloro-S5-methoxy-1-[4-(pyridin-2-yl)piperazin-1-yl]-5,6-dihydro-4H-[1,2,A4]triazolo[4, 3-a][1]benzazepine

JN V

QN A “OA a) 8-chloro-1-[4-(pyridin-2-yl)piperazin-1-yl]-4H-[1,24]triazolo[4,3-a][1 benzazepin-5 (6H)-one

CT AT

[00835] The title compound was prepared from 8'-chloro-1"-[4-(pyridin-2-yl)piperazin-1-11]-4'H,6'H-spiro[1,3- dioxolane-2.5"-[1,24]triazolo[4,3-a][1]benzazepine] (Example 171) according to the method described in Example 48. MS (ESI) m/z 395.1 ( M+H)*. b 8-chloro-1-[4-(pyridin-2-yl)piperazin-1-11]-5,6-dihydro-4H-[1,2A]triazolo 4,3-a][1 Ibenzazepin -5-ol ss | Ps Cc oH

[00836] The title compound was prepared from 8-chloro-1-[4-(pyridin-2-yl)piperazin-1-11)-4H-[1,2,4]triazolo[4,3-a ][1]benzazepin-S(6H)-one (Step a) of Example 232) according to the method described in Example 49. MS (ESD m/z 397.2 (M+H)*.c) 8- chloro-S-methoxy-1-[4-(pyridin-2-yl)piperazin-1-111-5,6-dihydro-4H-[1,2,4-triazolo[4,3-a][1] ]|benzazepine

[00837] The title compound was prepared from 8-chloro-1-[4-(pyridin-2-yl)piperazin-1-11]-5,6-dihydro-4H-[1,2,4 ]triazolo[4,3-

a][1]benzazepin-5-ol (Step b) of Example 232) according to the method described in Example 50. MS (ESI) m/z 411.3 (M+H)*.

Example 233 8-Chloro-1-(trans-4-ethyl-4-methoxycyclohexyl)-N,N-dimethyl-5,6-dihydro-4H-[1,2,4]triazolo[4,3 -a]|[1]/benzazepin-5-amine

ONLY AT THE

a) 8-Chloro-1-(trans-4-ethyl-4-methoxycyclohexyl)-5,6-dihydro-4H-[1,2,4-triazolo[4,3-a][1 Ibenzazepin -5-yl | tert-butyl carbamate /

NIX cl

[00838] The title compound was prepared from fert-butyl (7-chloro-2-OxO-2,3,4,5-tetrahydro-1H-1I-benzazepin-4-yl)carbamate (Intermediate 5) and 4-ethyl-4-methoxycyclohexane-carbohydrazide (Step b) of Intermediate 127) according to the method described in Method B of Example 5. MS (ESD m/z 475.3 (M+H)*.b ) 8-Chloro-1-(trans-4-ethyl-4-methoxycyclohexyl)-5,6-dihydro-4H-[1,24]triazolo 4,3-a][1 Ibenzazepin-5- the mine

[00839] The title compound was prepared from [8-chloro-1-(trans-4-ethyl-4-methoxycyclohexyl)-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepin-5-yl]fert-butyl carbamate (Step a) of Example 233) according to the method described in Example 2. MS (ESI) m/z 375.1 ( M+H)*. c) 8-chloro-1-(trans-4-ethyl-4-methoxycyclohexyl)-N N-dimethyl-5,6-dihydro-4H-1,2A]triazolo[4,3-a] [1 Ibenzazepin-5-amine

[00840] The title compound was prepared from 8-chloro-1-(trans-4-ethyl-4-methoxycyclohexyl)-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1|benzazepin-5-amine (Step b) of Example 233) according to the method described in Example 101. MS (ESI) m/z 403.3 (M+H)*.

Example 234 8-Chloro-1-(trans-4-ethoxy-4-methylcyclohexyl)-N,N-dimethyl-5,6-dihydro-4H-[1,2,4]triazolo[4,3 -a][1]/benzazepin-5-amine VA)

Or a) 8-Chloro-1-(trans-4-ethoxy-4-methylcyclohexyl)-5,6-dihydro-4H-[1,2,4-triazolo[4,3-a][1 Ibenzazepin-5-yl | tert-butyl carbamate 7

[00841] The title compound was prepared from tert-butyl (7-chloro-2-OxO-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate (Intermediate 5 ) and trans-4-ethoxy-4-methylcyclohexane-carbohydrazide (Step b) of Intermediate 128) according to the method described in Method B of Example 5. MS (ESD) m/z 475.3 (M+H )*. b) 8-chloro-1-(trans-4-ethoxy-4-methylcyclohexyl)-5,6-dihydro-4H-[1,2A]triazolo 4,3-a][1Ibenzazepin-5 -amine 7

[00842] The title compound was prepared from [8-chloro-1-(trans-4-ethoxy-4-methylcyclohexyl)-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepin-5-yl |fert-butyl carbamate (Step a) of Example 234) from

314/323 according to the method described in Example 2. MS (ESI) m/z 375.2 (M+H)*. c) 8-chloro-1-(trans-4-ethoxy-4-methylcyclohexyl)-N N-dimethyl-5,6-dihydro-4H-1,2A]triazolo[4,3-a] [1]benzazepin-5-amine

[00843] The title compound was prepared from 8-chloro-1-(trans-4-ethoxy-4-methylcyclohexyl)-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1]benzazepin-5-amine (Step b) of Example 234) according to the method described in Example 101. MS (ESI) m/z 403.3 (M+H)*. Example 235 8'-Chloro-1'-[trans-4-methoxy-4-(trifluoromethylcyclohexyl]-4H,6'H-spiro| 1,3-dioxolane-2.5"-1,2,A4 ]triazolo[4,3-a][1]benzazepine So

[00844] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and trans-A-methoxy-4-(trifluoromethyl)cyclohexanecarbohydrazide — (Intermediate 124) according to the method described in Example 108. MS (ESI) m/z 458.2 (M+H)* Example 236 8 '-Chloro-1'-[cis-4-methoxy-4-(trifluoromethylcyclohexyl]-4'H,6'H-spiro 1,3-dioxolane-2.5"-1,2,A]triazolo[ 4,3-a][1]benzazepine TO a So

[00845] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and cis-4-methoxy-4-(trifluoromethyl)cyclohexanecarbohydrazide (Intermediate 123) according to the method described in Example 108. MS (ESI) m/z 458.2 (M+H)*.

315 /323 Example 237 8'-Chloro-1'-(trans-4-ethoxy-4-methylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1] ,2,4]triazolo[4,3-a][1]benzazepine dA

XI ONLY

[00846] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and trans-4-ethoxy-4-methylcyclohexane-carbohydrazide (Step b) of Intermediate 128) according to the method described in Example 190. MS (ESI) m/z 418.2 (M+H)*. Example 238 8'-Chloro-1'-(trans-4-ethoxy-4-propylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2, 4]triazolo[4,3-a][1]benzazepine

VA O < O,”

[00847] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and 4-ethoxy-4-propyl-cyclohexanecarbohydrazide (Step d) of Intermediate 129) according to the method described in Example 190. MS (ESI) m/z 446.3 (M+H)*. Example 239 8'-Chloro-1'-[1-(pyridin-2-ylmethyl)pyrrolidin-3-11]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1] ,2,4]triazolo[4,3-a][1]benzazepine Ox

Oh! O. 7 ci

[00848] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and 1-(pyridin-2-ylmethyl)pyrrolidine-3-carbohydrazide (Step b) of Intermediate 116) according to the method described in Example 190. MS (ESI) m/z 438.3 (M+H)*. Example 240 8'-Chloro-1'-(cis-4-ethyl-4-methoxycyclohexyl)-4'H,6'H-spiro 1,3-dioxolane-2.5"-1,2A]triazole [4,3-a][1]benzazepine

SS and Example 241 8'-Chloro-1'-(trans-4-ethyl-4-methoxycyclohexyl)-4'H,6'H-spiro)| 1,3-dioxolane-2,5'-1,2,A4]triazolo[4,3-a][1]benzazepine

only The

[00849] The title compounds were prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and 4-ethyl-4-methoxycyclohexane-carbohydrazide (Step b) of Intermediate 127) according to the method described in Example 190. The cis and trans isomers were separated by flash column chromatography using dichloromethane:methanol = 9:1 as eluent. MS (ESI) m/z 418.2 (M+H)*. Example 242 8'-Chloro-1'-(trans-4-methoxy-4-propylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2, 4]triazolo[4,3-a][1]benzazepine

317 /323 o > Ox

SO from Example 243 8'-Chloro-1'-(cis-4-methoxy-4-propylcyclohexyl)-4'H,6'H-spiro) | 1,3-dioxolane-2.5"-1,2,4]triazolo[4,3-a][1]benzazepine

SD

[00850] The title compounds were prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and d4-methoxy4-propyl-cyclohexanecarbohydrazide (Step b) of Intermediate 130) according to the method described in Example 190. The cis and trans isomers were separated by flash column chromatography using dichloromethane:methanol = 95:5 as eluent. . MS (ESI) m/z 432.2 (M+H)*. Example 244 8-Chloro-1-(trans-4-ethoxy-4-ethylcyclohexyl)-N-(propan-2-yl)-5,6-dihydro-4H-[1,2,4]triazole [4,3-a][1]benzazepin-5-amine

GO

OO a) [8-Chloro-1-(trans-4-ethoxy-4-ethylcyclohexyl)-5,6-dihydro-4H-[1,24]triazole 4,3-a][1 Ibenzazepin -5-yl | tert-butyl carbamate

AT

OS NHBoc

318 /323

[00851] The title compound was prepared from tert-butyl (7-chloro-2-OxO-2,3,4,5-tetrahydro-1H-1-benzazepin-4-yl)carbamate (Intermediate 5 ) and trans-4-ethoxy-4-ethylcyclohexane-carbohydrazide (Step c) of Intermediate 126) according to the method described in Method B of Example 5. MS (ESI) m/z 489.3 (M+H )*. b 8-chloro-1-(trans-4-ethoxy-4-ethylcyclohexyl)-5,6-dihydro-4H-[1,2,4-triazolo[4,3-a][1]|benzazepin -5-amine

AT THE O I S AND

[00852] The title compound was prepared from [8-chloro-1-(trans-4-ethoxy-4-ethylcyclohexyl)-5,6-dihydro-4H-[1,2,A]triazole [4,3-a][1]benzazepin-5-yl] tert -butyl carbamate (Step a) of Example 244) according to the method described in Example 2. MS (ESI) m/z 389.3 ( M+H)*. c) 8-chloro-1-(trans-4-ethoxy-4-ethylcyclohexyl)-N-(propan-2-yl)-5,6-dihydro-4H-1,2A]ltriazolo[4 ,3-a][1]benzazepin-5-amine

[00853] The title compound was prepared from 8-chloro-1-(trans-4-ethoxy-4-ethylcyclohexyl)-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1]|benzazepin-5-amine (Step b) of Example 244) according to the method described in Example 24. MS (ESI) m/z 431.3 (M+H)*.

Example 245 8-Chloro-1-(trans-4-ethoxy-4-ethylcyclohexyl)-NV,N-dimethyl-5,6-dihydro-4H-[1,2,4]triazolo[4,3 -a][1]benzazepin-5-amine

GIVES

AI Er d

[00854] The title compound was prepared from 8-chloro-1-(trans-4-ethoxy-4-ethylcyclohexyl)-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1]benzazepin-5-amine (Step b) of Example 244) according to the method described in

Example 101. MS (ESI) m/z 417.3 (M+H)*. Example 246 8'-Chloro-1'-[(3R)-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl]-4'H,6'H-spiro 1,3-dioxolane-2.5" - 1,2,A]triazolo[4,3-a][1]benzazepine Do

W SS

[00855] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and (3R)-1-(pyridin-2-ylmethyl)pyrrolidine-3-carbohydrazide (Step b) of Intermediate 131) according to the method described in Example 190. MS (ESD m/z 438.1 (M+H )* Example 247 8-Chloro-5-methoxy-1-[(3R)-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl1]-5,6-dihydro-4H-[1,2 ,A4]triazolo[4,3-a][1]benzazepine

No

[00856] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and ( 3R)-1-(pyridin-3-ylmethyl)pyrrolidine-3-carbohydrazide (Step b) of Intermediate 133) according to the method described in Example 108. MS (ESD m/z 410.1 (M+H)* Example 248 8-Chloro-S-methoxy-1-[(3R)-1-(pyridin-2-ylmethyl-pyrrolidin-3-yl]-5,6-dihydro-4H-[1,2,4] triazolo[4,3-a][1]benzazepine

the er the

320 / 323

[00857] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and ( 3R)-1-(pyridin-2-11methyl)pyrrolidine-3-carbohydrazide (Step b) of Intermediate 131) according to the method described in Example 108. MS (ESD m/z 410.2 (M+H)* .

Example 249 8'-Chloro-1'-[(3S)-1-(pyridin-3-ylmethyl-pyrrolidin-3-yl]-4'H,6'H-spiro[1,3-dioxolane-2,5'- [1,2,4]triazolo[4,3-a][1]benzazepine O. RW / OO cr 1 SS

[00858] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and (3S)-1-(pyridin-3-ylmethyl)pyrrolidine-3-carbohydrazide (Step b) of Intermediate 134) according to the method described in Example 190. MS (ESD m/z 438.1 (M+H )*.

Example 250 8'-Chloro-1'-[(3R)-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-4'H,6'H-spiro[1,3-dioxolane-2,5 '-[1,2,4]triazolo[4,3-a][1]benzazepine Us cr O

[00859] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2"-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and (3R)-1-(pyridin-3-ylmethyl)pyrrolidine-3-carbohydrazide (Step b) of Intermediate 133) according to the method described in Example 190. MS (ESD m/z 438.1 (M+H )*.

Example 251 8-Chloro-S5-methoxy-1-[(3S)-1-(pyridin-3-ylmethyl-pyrrolidin-3-

321 /323 i1]-5,6-dihydro-4H-ral triazolo[4,3-a][1]benzazepine — FP clo

[00860] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and ( 3S)-1-(pyridin-3-ylmethyl)pyrrolidine-3-carbohydrazide (Step b) of Intermediate 134) according to the method described in Example 108. MS (ESD m/z 410.1 (M+H)* Example 252 8'-Chloro-1'-[(3S)-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl]-4'H,6'H-spiro[1,3-dioxolane-2, 5'-[1,2,A4]triazolo[4,3-a][1]benzazepine Os =) x Ox N o cy E?

[00861] The title compound was prepared from 7-chloro-1,5-dihydrospiro[1-benzazepine-4,2'-[1,3]dioxolan]-2(3H)-one (Intermediate 53) and (3S5)-1-(pyridin-2-ylmethyl)pyrrolidine-3-carbohydrazide (Step b) of Intermediate 132) according to the method described in Example 190. MS (ESD) m/z 438.1 (M+ H)*. Example 253 8-Chloro-S5-methoxy-1-[(3S)-1-(pyridin-2-ylmethyl-pyrrolidin-3-yl]-5,6-dihydro-4H-el-triazolo[4,3-a] [1]benzazepine

N "the AN

LA or

[00862] The title compound was prepared from 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (Step d) of Intermediate 103) and ( 3S)-1-(pyridin-2-ylmethyl)pyrrolidine-3-carbohydrazide (Step b) of

322/323 Intermediate 132) according to the method described in Example 108. MS (ESID) m/z 410.1 (M+H)*.

[00863] The following formulation examples illustrate representative pharmaceutical compositions of this invention. The present invention however is not limited to the following pharmaceutical compositions. A) Solid oral dosage forms

1. Tablets Active substance(s) 0.01 — 90% Filler 1-— 99.9% Binder 020% Disintegrant 0— 20% Lubricant 0- 10% Other excipient(s) 0 50% specific(s) II. Orodispersible Films Active substance(s) 0.01 — 90% Film-forming agent 1-— 99.9% Plasticizer 040% Other excipient(s) 0— 50% specific(s) B) Liquid Oral Dosage Forms III. Oral suspensions Active substance(s) 0.01 — 50% Liquid carrier 10 — 99.9% Wetting agent 0— 50% Thickener 0 — 50% Buffering agent qs. Osmotic agent 0 — 50% Preservatives q.s. IV. Syrups Active substance(s) 0.01 — 50% Solvent 10 — 99.9% Sugar component 1-20% Flavoring agents 0- 10% C) Parenteral dosage forms V. Intravenous injections Active substance(s) (s) 0.01 — 50% Solvent 10 — 99.9% Co-solvent 0 99.9% Osmotic agent 050% Buffering agent qs D) Other Dosage Forms VI. Suppositories Active substance(s) 0.01 — 50% Suppository base 1 99.9% Surfactants 020% Lubricants 020%

323 / 323 Preservatives qs.

VII.

Eye drops Active substance(s) 0.01 — 50% Water 0 99.9% Solvent 0 99.9% Osmotic agent 0-20% Viscosity enhancer 020% Buffering agent qs.

Preservatives qs.

Claims (53)

1. Compound, characterized by the fact that it has the general formula OD to Dr STEEL. R° wherein ring A is a cycloalkyl or heterocyclyl group; Y is -O-, -C(O)-, -CH7-, -NH-, -C14alkyl-N(R')- or bond if ring B is present; or -N(C1,alkyl)o, C(O)OCr,4alkyl, C1,4alkyl optionally substituted with halogen, C1,4alkoxy group or halogen if ring B is not present; ring B is an optionally substituted heteroaryl, aryl or heterocyclyl group; or BYA- conjointly represents a 3H-spiro[2-benzofuran-1 4'-piperidin-1"-yl]; or the "O. or "O." group or group; R' is a hydrogen, halogen, C, 1.1alkyl, C11alkoxy, CF3 or CN; Rº? is a hydrogen or C,alkyl group; R? is an NRR;, OR” or halogen group; or R? and R? together represent -O-(CH2)-O group -, 0xO or =N-OH; Rº and Rº are independently a hydrogen; C1,alkyl optionally substituted with OH group, halogen, cycloalkyl, optionally substituted aryl or NRºRº; Cy!; C(O)R'; -S group (O0:)R"º* or C2. 1alkynyl; or R° and R6 taken together with the N to which they are attached form a heterocycle; Rº is a hydrogen; C1 4 alkyl optionally substituted with OH, halogen, Cy', Cyaalkoxy, -S(O)>-Cyalkyl or NRUR"? group; C(O)R"3; Si(CH;3)2-r-butyl or Co,alkynyl group; R' is a C1,alkyl optionally substituted with OH, CN, halogen, Cy? or NRUR"”?; Cr,alkoxy, Co 1alkenyl, Cy? or N(C 4alkyl) group; R$ and Rº is independently a hydrogen, group C, ,alkyl or C(O)OR?!; R'° is a C1,4alkyl, OH or NRYR group"; R" and R1' is independently a hydrogen or C.1 alkyl group; or R"' and R*' taken together with the N to which they are attached form an optionally substituted heterocycle; R"? is a C1,4 alkyl optionally substituted with CN or NR1R" group; Cy? or NR1R"! group; R'*º and RU is independently a hydrogen or C.1 alkyl group; R'º and RU is independently a hydrogen, Cr group. 4alkyl, or optionally substituted aryl; or R'º and RU taken together with the N to which they are attached form a heterocycle; R'º and R? is a hydrogen or C₁₋₆alkyl group; R"" and R* is independently a hydrogen or Cr.aalkyl group; Cy! is an optionally substituted cycloalkyl, heterocyclyl or heteroaryl group; Cy is an optionally substituted aryl or cycloalkyl group; Cy? is an optionally substituted aryl, cycloalkyl, heterocyclyl or heteroaryl group; X is a C, ,alkyl, aryl or heteroaryl group; Z is a C1 alkyl group; m2,3,40u5 and/or salts thereof and/or geometric isomers thereof and/or stereoisomers thereof and/or enantiomers thereof and/or racemates thereof and/or diastereomers thereof and/or biologically active metabolites thereof and/or prodrugs thereof and/or solvates thereof and/or hydrates thereof and/or polymorphs thereof. 2. Compound according to claim 1, characterized in that R' is a hydrogen, fluorine, chlorine, bromine, methyl, methoxy, CF; or CN. 3. Compound according to claim | or 2, characterized in that ring A is a 3 to 6 membered saturated carbocyclic group or a 4 to 7 membered saturated heterocycle containing 1 or 2 N; ring B is an optionally substituted 5 or 6 membered monoheteroaryl, 6 to 10 membered aromatic carbocycle, or saturated, monocyclic, bicyclic, fused and/or bridged 4 to 7 membered heterocycle containing 1, 2 or 3 heteroatoms selected from O, S or N; or B-Y-A- together represents a 3fH-spiro[2-benzofuran-1,4'-piperidin-1"-yl]; or PD the TC group YO. or group "QU, or group o. X is isopropyl group; Z is methyl group. A compound according to any one of claims 1 to 3, characterized in that ring B is an optionally substituted 6-membered monoheteroaryl group, or 5- to 6-membered saturated monocyclic heterocycle containing 1 or 2 heteroatoms selected from among O, S or N. 5. Compound according to any one of claims 1 to 4, characterized in that Y is -O-, -C(O0)-, -CH7-, -NH-, -Cr. alkyl-N(R'º)- or a single bond if ring B is present and R"º is hydrogen or methyl group. 6. Compound according to any one of claims 1 to 5, characterized in that ring A is a 4 to 6 membered saturated carbocyclic group or a 4 to 7 membered saturated heterocycle containing 1 or 2 N fixed via a nitrogen on the Y ring or the triazole ring of the 5,6-dihydro-4H-[1,24]triazolo[4,3-a][1]benzazepine nucleus. A compound according to any one of claims 1 to 6, characterized in that ring A is cyclohexyl, Y is -O-, ring B is pyridin-2-yl and R' is chloro. A compound according to any one of claims 1 to 6, characterized in that ring A is piperidine, piperazine, or pyrrolidine, Y is -O-, -C(O)-, -CH,-, or a bond ring B is pyridine, piperidine, tetrahydrofuran, or tetrahydropyran, and R' is chloro. A compound according to any one of claims 1 to 3, characterized in that Y is -N(Cr-4alkyl), C(O)OC ,4alkyl, C14alkyl optionally substituted with halogen, C14alkoxy group or halogen and ring B is not present. 10. Compound according to claim 9, characterized in that ring A is a 4- to 6-membered saturated carbocyclic group. 11. A compound according to claim 10, characterized in that Y is a group selected from the group consisting of - N(Ci4alkyl), C(0)OC ,alkyl, C1,alkyl optionally substituted with halogen, C group ., alkoxy and halogen. 12. Compound according to claim 10, characterized in that Y are two groups selected from the group consisting of C, , alkyl optionally substituted with halogen, C 1, alkoxy group and halogen. 13. Compound according to any one of claims 1 to 12, characterized in that Rº is a hydrogen or C ,4 alkyl group; R? is an NRR group'; R' and R6 are independently a hydrogen; C1,4 alkyl group optionally substituted with OH group, halogen, cycloalkyl, optionally substituted aryl or NRºR'º; Cy!; COLOR'; -S(O»)R"* or Cz. aalkynyl group; or Rº and R6 taken together with the N to which they are attached form a heterocycle; R' is a C1,alkyl group optionally substituted with OH, CN, halogen, Cy? or NRUR"?; Cr4alkoxy, Kaalkenyl,Cy? or N(C 1 4alkyl); R* and R are independently hydrogen, Cr,alkyl or C(OO)OR*'; R"º is a C r,4alkyl, OH or NRR group""; R'" and R* are independently a hydrogen or Cr.1alkyl group; or R"' and R'? taken together with the N to which they are attached form an optionally substituted heterocycle; R"°R" is independently a hydrogen or Cx.alkyl group; R°' is a hydrogen or C1,1 alkyl group; Cy' is an optionally substituted cycloalkyl, heterocyclyl or heteroaryl group; Cy? is an optionally substituted aryl, cycloalkyl, heterocyclyl or heteroaryl group. 14. Compound according to claim 13, characterized in that R? it's a hydrogen. 15. Compound according to claim 14, characterized in that Rº and R is independently a hydrogen; C(O)Rº; Cr. 1alkyl optionally substituted with OH group, halogen, cycloalkyl, optionally substituted aryl or NRºRº; Rº and Rº are independently hydrogen or C,alkyl group. 16. Compound according to claim 15, characterized in that Rº and Rº are hydrogens. 17. Compound according to claim 15, characterized in that Rº is a hydrogen, Ró is a Ci,alkyl group. 18. Compound according to claim 15, characterized by the fact that Rº and Ró are C,.,alkyl groups. 19. Compound according to claim 15, characterized in that Rº is a hydrogen; R is a C(O)R' group; R' is a C14 alkyl optionally substituted with OH, CN, halogen, Cy? or NRUR"?; Cr,4alkoxy, Cr,1alkenyl,Cy? or N(C,1alkyl) group; R!' and R?º are independently a hydrogen or Cr.1alkyl group; or R"' and R!? taken together with the N to which they are attached form an optionally substituted heterocycle; Cy? is an optionally substituted aryl, cycloalkyl, heterocyclyl or heteroaryl group. 20. Compound according to claim 14, characterized in that Rº is a hydrogen, Rº is a Cy! and Cy! is an optionally substituted cycloalkyl, heterocyclyl or heteroaryl group. 21. Compound according to claim 14, characterized in that Rº is a hydrogen or C,alkyl group; R” is an S(O2)R'º group; R'º is a C, ,4alkyl, OH or NRÚR group; R'* and Rº is independently a hydrogen or Cr.1alkyl group. 22. Compound according to claim 14, characterized in that Rº and Ró taken together with the N to which they are attached form a 4- to 7-membered heterocycle containing optionally 1, 2 or 3 heteroatoms selected from O, S or No. 23. Compound according to any one of claims 1 to 12, characterized in that Rº is a hydrogen or C1,alkyl group; R° is an OR group; Rº is a hydrogen; Cialkyl group optionally substituted with OH, halogen, Cy', C 1,4 alkoxy, -S(O);-Cr 4 alkyl or NRUR!' group; C(O)R"3, Si(CH;3)2-t-butyl or C 4alkynyl; R' and R"? is independently a hydrogen or C1 group. 1alkyl; or R"' and R' taken together with the N to which they are attached form an optionally substituted heterocycle; R" is a C1' alkyl group optionally substituted with a CN or NRR° group; Cy? or NR!R!"; R'º º RU is independently a hydrogen, group Cx. 1 optionally substituted alkyl or aryl; or R'* and R”º taken together with the N to which they are attached form a heterocycle; R"° and R° is independently a hydrogen or C.1 alkyl group; Cy' is an optionally substituted aryl or cycloalkyl group. 24. Compound according to claim 23, characterized in that R? it's a hydrogen. 25. Compound according to claim 24, characterized in that Rº is a hydrogen. 26. Compound according to claim 24, characterized by the fact that Rº is a Ci,alkyl group. 27. Compound according to claim 24, characterized in that R$ is a C(O)R"? group; R" is a C1.alkyl group optionally substituted with a CN or NRURº group; Cy group? or NR!R"; Re R" is independently an optionally substituted hydrogen, C,. 1alkyl or aryl group; or R'* and Rº taken together with the N to which they are attached form a heterocycle; R""* and Rº is independently a hydrogen or C1 group. 1 alkyl. 28. Compound according to any one of claims 13 to 27, characterized in that the absolute configuration of the carbon in position 5 in the nucleus 5,6-dihydro-4H-[1,2,4]triazolo[4, 3-a][1]benzazepine is (R. 29. A compound according to any one of claims 13 to 27, characterized by the fact that the absolute configuration of the carbon at position 5 in the 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine nucleus is ( S). 30. Compound according to any one of claims 1 to 12, characterized by the fact that Rº and R? together represent -O-(CH2)n-O-, oxo or =N-OH group, m is 2, 3,4 or 5. 31. Compound according to claim 30, characterized in that R? and R? together represent -O-(CH>), -O- and m is 2. 32. A compound according to any one of claims 1 to 31, characterized in that the compound is selected from the group consisting of: [8-chloro-1-[1-(pyridin-2-yl)piperidin-4- tert-Butyl 11]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a][1]benzazepin-5-yl]carbamate, 8-chloro-1-[1 -(pyridin-2-yl)piperidin-4-11]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a][1]benzazepine-5-amine, N- [8-chloro-[1-(pyridin-2-yl)piperidin-4-11]-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1]benzazepin -5-yl Jacetamide, N-(8-chloro-[1-(pyridin-2-yl)piperidin-4-11]-5,6-dihydro-4H-[1,24]triazolo[4, 3-a][1]benzazepin-5-11)-2-methylpropanamide, (8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro- 4H-[1,2,A]triazolo[4,3-a]benzazepine-5-yl] tert-butyl carbamate, 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl ]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepine-5-amine, (5S)-8-chloro-1-[trans-4 -(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1|benzazepine-5-amine, (5R) -8- chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1|benzazepine -5-amine, N-(8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4 ,3-a][1]benzazepin-5-yl)acetamide, N-(8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a ][1]benzazepin-5-yl |glycinamide, N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4 ,3-a][1]benzazepin-5-yl |glycinamide, N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4 ,3-a][1]benzazepin-5-yl |glycinamide, (25)-2-amino-N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A4]triazolo[4,3-a][1]benzazepin-5-11)-2-phenylacetamide, (2R)-2-amino-N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepin-5-11)-2-phenylacetamide, N-(8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a] [1]benzazepin-5-yl |-2-hydroxyacetamide, 3-(8-Chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a ][1]benzazepin-5-11)-1,1-dimethylurea, N-(8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a ][1]benzazepin-5-yl 1-Nº,Nº-dimethylglycinamide, N-(8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a ][1 ]|benzazepin-5-yl |methanesulfonamide, N-(8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a ][1]benzazepin-5-11)-N-methylmethansulfonamide, N'-(8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3- a][1-benzazepin-5-yl)-N,N-dimethylsulfamide, 8-Chloro-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3- a][1 |benzazepine-5-amine, 8-Chloro-N,N-dimethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4, 3-a][1]benzazepine-5-amine, 8-Chloro-N-ethyl-1-[trans-4-(pyridin-2-1loxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3- a][1]benzazepine-5-amine, 8-chloro-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di- hydro-4H-[1,2,A4]triazolo[4,3-a][1]benzazepine-5-amine, (5S)-8-chloro-N-(propan-2-yl)-1-[trans -4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1]|benzazepine-5-amine, (5R)-8-chloro-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1, 2,A4]triazolo[4,3-a][1]benzazepine-5-amine, 8-chloro-N-cyclobutyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5, 6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]Ibenzazepine-5-amine, 8-chloro-N-(oxetan-3-yl)-1-[trans -4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1]benzazepine-5-amine, 8 -chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-N-(tetrahydro-2H-pyran-4-11)-5,6-dihydro-4H-[1 ,2 A]triazolo[4,3-a][1]benzazepine-5-amine, 8-chloro-N-(4-4-difluorocyclohexyl)-1-[trans-4-(pyridin-2-yloxy) cyclohexyl]-5,6- dihydro-4H-[1,2A4]triazolo[4,3-a][1|benzazepine-5-amine, 8-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl ]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepine-5S-amine , 8-methoxy-N-(propan-2-yl) hydrochloride )-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1]| benzazepine-5-amine, (1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,A4]triazole [4,3-a][1]benzazepin-5-yl]carbamate — from — tert-butyl, 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)- hydrochloride 5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1]benzazepine-5-amine, N-N-dimethyl-1-[trans-4-(pyridin-2 -yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1 Ibenzazepine-5- the mine, N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2, A4]triazolo[4,3-a][1]benzazepine-5-amine, 8-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1 ]benzazepine-5-amine, 8-Methyl-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4] triazolo[4,3-a][1]benzazepine-5-amine, 8-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1 Benzazepine-5-amine, 8-bromo-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- [1,2,4]triazolo[4,3-a][1]/benzazepine-5-amine, 8-chloro-1-(3,3-difluorocyclobutyl)-N-(propan-2-yl)-5 ,6-dihydro-4H-[1,24]triazolo[4,3-a][1]benzazepine-5-amine, 8-chloro-1-(4,4-difluorocyclohexyl)-N- (propan-2-yl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine-5-amine, 8-chloro-1-[trans -4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1]Ibenzazepine-5-amine, 8-chloro-N- (propan-2-yl)-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1 ]|benzazepine-5-amine, 8-bromo-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3- a][1]|benzazepine-5-amine, 8-bromo-N-(propan-2-yl)-1-[trans-4-(trifuoromethyl)cyclohexyl]-5,6-dihydro-4H -[1,2,A4]triazolo[4,3-a][1|benzazepine-5-amine, 1'-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8' -(trifluoromethyl)-4'H,6'H-spiro[1,3-dioxolane-2,5"-[1,2,4]triazolo[4,3-a][1]benzazepine], 1-[ trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-4H-[1,2A]triazolo[4,3-a][1]benzazepin-5(6H)-one, 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6- dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepin-5-ol, S-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclo- hexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1]benzazepine, 5-(cyclopropylmethoxy)-1-[trans- 4-(pyridin-2-yloxy)cyclohexyl]-8-(trifluoromethyl)-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1]benzazepine, 5 -([tert-butyl(dimethyl)silylJoxy)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4]triazolo[4,3-a][1]benzazepine, 8'-chloro-1"-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'H-spiro[ 1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine], 8-chloro-1-[trans-4-(pyridin-2-yloxy) cyclohexyl]|-4H-[1,24]triazolo[4,3-a][1Ibenzazepin-5(6H)-one, 8-chloro-1-[trans-4-(pyridin-2-yloxy )cyclohexyl]-5,6-dihydro-4H-[1,2A4]triazolo[4,3-a][1]benzazepin-5-ol, (55)-8-chloro-1-[ trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1]benzazepin-5-ol, (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3- The] [1]benzazepin-5-ol, 8-chloro-5-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 ,A]triazolo[4,3-a][1]benzazepine, 5-(cyclopropylmethoxy)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di -hydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine, 2-((8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl ]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-ylJoxy)-N,N-dimethylethanamine, 8'-chloro-1 '-[trans-4-(trifluoromethyl)cyclohexyl]|-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3- a][1]benzazepine], 8'-bromo-1'"-[trans-4-(pyridin-2-yloxy)cyclohexyl |-4'H,6'H-spiro[1,3-dioxolane- 2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine], 1'-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4'H, 6'H-spiro[1,3- dioxolane-2,5'-[1,24]triazolo[4,3-a][1]benzazepine], 8-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]- 4H- [1,2 4]triazolo[4,3-a][1 Ibenzazepin-5(6H)-one, 8-bromo-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5, 6-dihydro- 4H-[1,2,A]triazolo[4,3-a][1]benzazepin-5-ol, 1'-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4'H, 6'H-spiro[1,3- dioxolane-2,5'-[1,24]triazolo[4,3-a][1]benzazepin]-8'-carbonitrile, (5S)-8-chloro-N N-dimethyl-1-[trans- 4-(pyridin-2-1loxy)cyclo- hexyl]-5,6-dihydro-4H-[1,2A4]triazolo[4,3-a][1|benzazepine-5-amine, (5S)-N-(8-chloro-1-[ trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di- hydro-4H-[1,2,4]triazolo[4,3-a][1Ibenzazepin-5-yl)acetamide, 8'-chloro-1'-[trans-4-(pyridin-2-ylmethyl)cyclo -hexyl --4'H,6'H- spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine], [trans-4-(8'-chloro-4'H,6 'H-spiro[1,3-dioxolane-2,5'- [1,2 A]triazolo[4,3-a][1]benzazepine]-1"-yl)cyclohexyl (pyrrolidin-1- 11)methanone, 8-chloro-1-[trans-4-(trifluoromethyl)cyclohexyl]|-4H- [1,24]triazolo[4,3-a][1Ibenzazepin-S(6H)-one, 8-chloro-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-di- hydro-4H- [1,2 4]triazolo[4,3-a][1 Ibenzazepin-5-ol, (cis)-8-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane- 2.5"- [1,24]triazolo[4,3-a][1]Ibenzazepin]-1"-11)-3-methyl-1-oxa-3- azaspiro[4.5]decan-2-one, 8-chloro-5-methoxy-1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-di- hydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine, (trans)-8-(8'-chloro-4'H,6'H-spiro[1,3- dioxolane-2.5"- [1,24]triazolo[4,3-a][1Ibenzazepin]-1"-11)-3-methyl-1-oxa-3- azaspiro[4.5]decan-2-one, N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di- hydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-11)-N-methylmethanesulfonamide, (5S)-8-chloro-N-ethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[ 4,3-a][1]benzazepine-5-amine, (5S)-8-chloro-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1]|benzazepine-5-amine, 8'-Chloro-1'-[1-(pyrimidin-2-yl)azetidin-3-11])-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1, 2 4]triazolo[4,3-a][1]benzazepine], N-((5S5)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24]triazolo[4, 3-a][1 Ibenzazepin-5-11)-4-fluorobenzamide, 8'-bromo-1'"-[trans-4-(trifluoromethyl)cyclohex11]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4] triazolo[4,3-a][1]benzazepine], 5-(Propan-2-ylamino)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[ 4,3-a][1]|benzazepin-8-carbonitrile, (5S)-8-chloro-N-(4-fluorobenzyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4 ]triazolo[4,3-a][1 |benzazepine-5-amine, 1º-[trans-4-(trifluoromethyl)cyclohexyl]-4'H,6'ºH-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3- a][1]benzazepine]-8'-carbonitrile, [trans-4-(8'-bromo-4'H,6'H-spiro[1,3-dioxolane-2,5'- [1,2 4]triazolo[4,3-a][1 |benzazepin]-1"-yl)cyclohexyl ]|(piperidin-1-yl)]methanone, trans-4-(8-bromo-5-OxO-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-yl)cyclohexane methyl carboxylate, 8-bromo-1-[trans-4-(piperidin-1-ylcarbonyl)cyclohexyl]-4H-[1,24]triazolo[4,3-a][1 Ibenzazepin-5(6H)-one, 8'-chloro-1"-[trans-4-(trifluoromethyl)cyclohexyl]-4'H,6'H-spiro[1,3-dioxane-2,5'-[1,2,4]triazole [4,3-a][1]benzazepine], 1'-[trans-4-(piperidin-1-ylcarbonyl)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[ 4,3-a][1]benzazepin]-8'-carbonitrile, 8'-chloro-1"-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'H- spiro[1,3-dioxane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine], 8-bromo-1-[trans-4-(trifluoromethyl)cyclo- hexyl |-4H-[1,24]triazolo[4,3-a][1 Ibenzazepin-5(6H)-one, [trans-4-(8-bromo-5-hydroxy-5,6-di- hydro-4H-[1,24]triazolo[4,3-a][1Ibenzazepin-1-yl)cyclohexyl]|(piperidin-1-yl)]methanone, 8-bromo-1-[trans- 4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepin-5-ol, 1'-(1, 4'"-bipiperidin-1"-11)-8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3 -a][1]benzazepine], [1-(14'-bipiperidin-1"-11)-8-chloro-5,6-dihydro-4H-[1,2A]triazolo[4,3 -a][1]benzazepin-5-yl | tert -butyl carbamate, 8'-fluoro-1"-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4'H,6'H - spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine], (5S)-8-chloro-N-(4-fluorobenzyl) -N-methyl-1 -[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A4]triazolo[4,3-a][1]benzazepin-5-amine , N-((58)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1|benzazepin-5-yl|prop-2-enamide, (5R)-8-chloro-N-ethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl ]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine, (5R)-8-chloro-N-methyl-1- [trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1 Ibenzazepin-5-amine, (5R)-8-chloro-N,N-dimethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4] triazolo[4,3-a][1]|benzazepin-5-amine, 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4H-[1,2A]triazolo[4,3 - al[1]benzazepin-S5(6H)-one, (55)-8-chloro-S-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]- 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1|benzazepine, (5R)-8-chloro-5-methoxy-1-[trans-4-( pyridin-2-yloxy)cyclohexyl]- 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine, 8-chloro-5-(propan-2-yloxy)-1-[trans-4 -(pyridin-2-yloxy)cyclo- hexyl]-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1]benzazepine, 8'-chloro-1"-[trans-4-(pyridin-2- yloxy)cyclohexyl|-4'H,6'H- spiro[1,3-dioxepane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine], 1-[trans-4-(pyridin-2-yloxy)cyclo- hexyl]-5,6-dihydro-4H- [1,2 4]triazolo[4,3-a][1 Ibenzazepin-5-ol, [trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2] .5"- [1,2 A]triazolo[4,3-a][1]benzazepin]-1"-yl)cyclohexyl J|(morpholin-4-yl)]methanone 5S-methoxy-1-[trans-4- (pyridin-2-yloxy)cyclohexyl]-5,6-dihydro- 4H-[1,24]triazolo[4,3-a][1]benzazepine, 8-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4H- [1,2 A]triazolo[4,3-a][1]benzazepin-5(6H)-one, 8-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5 ,6-dihydro- 4H-[1,2,A]triazolo[4,3-a][1]benzazepin-5-ol, (8-chloro-1-[trans-4-(morpholin-4-yl)cyclohexyl]- 5,6-dihydro- 4H-[1,2,A]triazolo[4,3-a][1]benzazepin-5-yl | tert-butyl carbamate, 8-chloro-1-[trans-4-(morpholin-4-yl) cyclohexyl]-5,6-dihydro-4H- [1,2 4]triazolo[4,3-a][1 Ibenzazepin-5-amine, 8-chloro-1-[trans-4-(morpholin-4-yl)cyclohexyl]-N-(propan- 2-il)- 5,6-dihydro-4H-[1,2A4]triazolo[4,3-a][1Ibenzazepin-5-amine, (5r,8r)-8-(8'-chloro-4'H, 6'H-spiro[1,3-dioxolane-2,5'- [1,2 4]triazolo[4,3-a][1 Ibenzazepin]-1"-11)-2-(propan-2-yl)-2- azaspiro[4,5]decan-11-one, (5r,8r)-8-(8-chloro-5-hydroxy-5,6-dihydro-4H- [1,2 A]triazolo[4,3-a][1]benzazepin-1-yl)-2-(propan-2-11)-2- azaspiro[4,5]decan-1-one, (5S)-8-chloro-1-[trans-4-(pyridin-2-1loxy)cyclohexyl]-5-(pyrrolidin-1-11)-5 ,6-dihydro-4H-[1,24]triazolo[4,3-a][1]benzazepine, N-((58)-8-chloro-1-[trans-4-(pyridin-2) -yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]|benzazepin-5-11)-2,2-dimethylpropanamide, N-((58)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4 ,3-a][1 Ibenzazepin-5-yl]cyclopropanecarboxamide, N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di - hydro-4H-[1,2,4]triazolo[4,3-a][1|benzazepin-5-11)-2-methylpropanamide, N-((55)-8-chloro-1-[trans- 4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1Ibenzazepin-5-yl]cyclobutanecarboxamide, (5S )-8-chloro-5-(morpholin-4-11)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2, A]triazolo[4,3-a][1]benzazepine, N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di - hydro-4H-[1,2A4]triazolo[4,3-a][1]benzazepin-5-yl)-2,2-dimethylpropanamide, N-((SR)-8-cl oro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin -5-11)-2-methylpropanamide, N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- [1,2,4]triazolo[4,3-a][1]benzazepin-5-yl |cyclobutanecarboxamide, N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy) )cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]|benzazepin-5-11|cyclopropanecarboxamide, (5S)-8-chloro -5-(piperidin-1-11)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A4]triazolo[4, 3-a][1]benzazepine, (5S)-N-(butan-2-11)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6- dihydro-4H-[1,2,4]triazolo[4,3-a][1]|benzazepin-5-amine, (5s,8s)-8-(8'-chloro-4'H,6 'H-spiro[1,3-dioxolane-2,5'-[1,2-4]triazolo[4,3-a][1Ibenzazepin]-1"-yl)-2-(propan-2-yl) -2-azaspiro[4,5]decan-1-one, 8-chloro-5-methoxy-1-[trans-4-(morpholin-4-yl)cyclohexyl]-5,6-di- hydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine, 8-chloro-5-ethoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl] -5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine, (5R)-8-chloro-5-methoxy-1-[trans-4- (trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1|benzazepine, (55)-8-chloro-5-methoxy- 1-[trans-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1|benzazepine, 8-fluoro-5 -methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1] benzazepine, 8-chloro-N-(propan-2-yl)-1-[1-(pyridin-2-yl)piperidin-4-11]-5,6-dihydro-4H-[1.2A ]triazolo[4,3-a][1]|benzazepin-5-amine, 2-((8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6- dihydro-4H-[1,2,A4]triazolo[4,3-a][1]benzazepin-5-ylJoxy)ethanol, (55)-8-chloro-N,N-diethyl-1-[ trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepin-5-amine, 8-Chloro-N-methyl-N-(propan-2-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1, 2 A4]triazolo[4,3-a ][1]benzazepin-5-amine, (8-chloro-1-[4-(3-chloropyridin-2-yl)piperazin-1-yl]-5,6-dihydro-4H-[1,2 ,A]triazolo[4,3-a][1]benzazepin-5-yl] tert-butyl carbamate, 4-(8-chloro-5S-methoxy-5,6-dihydro-4H-[1, tert-butyl 2,4]triazolo[4,3-a][1]benzazepin-1-yl)piperidine-1-carboxylate, N-((5R)-8-chloro-1-[trans-4-( pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1-Ibenzazepin-5-11)-D-valinamide, ( 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1 Ibenzazepin-5-yl |) tert-butyl carbamate, (8-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[ tert-Butyl 4,3-a][1]benzazepin-5-yl]carbamate, 1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H- [1,24]triazolo[4,3-a][1]|benzazepin-5-amine, 8-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6 -dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepin-5-amine, 8-fluoro-N-(propan-2-yl)-1-[trans- 4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a][1]benzazepin-5-amine, 8- fluoro-N,N-dimethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3- a][1|benzazepin-5-amine, N N-dimethyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2, 4]triazolo[4,3-a][1 Ibenzazepin-5-amine, 8'-fluoro-1"-[trans-4-(trifluoromethyl)cyclohexyl]|-4'H,6'H-spiro[ 1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine], N-(propan-2-yl)-1-[trans-4-( pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1|benzazepin-5-amine, N-((55) )-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3-a] [1]|benzazepin-5-yl)tetrahydro-2H-pyran-4-carboxamide, N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl ]-5,6-di-hi dro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-11)-2-methylbutanamide, N-((55)-8-chloro-1-[trans-4 -(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepin-5-yl +-No. -dimethyl-B-alaninamide, (5S)-8-chloro-N-cyclopentyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1 ,2,4]triazolo[4,3-a][1]benzazepin-5-amine, 8'-chloro-1"-(1'H,3H-spiro[2-benzofuran-1 4'-piperidin]- 1"-11)- 4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine], 8- chloro-1-(1'H,3H-spiro[2-benzofuran-1 4'-piperidin]-1"-yl)-4H-[1,2,A]triazolo[4,3-a][1] |benzazepin-5(6H)-one, 8'-chloro-1'-[4-(pyridin-2-yloxy)piperidin-1-11)-4'H,6'H-spiro[1,3-dioxolane -2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine], N-((5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4 ,3-a][1]benzazepin-5-11)-2,2-dimethylbutanamide, N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4 ,3-a][1]benzazepin-5-11)-2-hydroxy-2-methylpropanamide, (5S)-8-chloro-N-ethyl-N-methyl-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2, 4]triazolo[4,3-a][1]benzazepin-5-amine, (5S)-8-chloro-N-(2-methylpropyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4 ]triazolo[4,3-a][1 Ibenzazepin-5-amine, 8'-Chloro-1'-[trans-4-(morpholin-4-yl)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1] ,2,4]triazolo[4,3-a][1]benzazepine], 8-Chloro-N,N-dimethyl-1-(1'H,3H-spiro[2-benzofuran-1,4"-piperidin]-1"'-yl)-5,6-dihydro-4H- [1,2 A]triazolo[4,3-a][1 |benzazepin-5-amine, 8'-Chloro-1"'-[4-(3-chloropyridin-2-yl)piperazin-1-11)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[ 1,2,4]triazolo[4,3-a][1]benzazepine], (55)-8-chloro-N-(2,2-dimethylpropyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1, 2 A4]triazolo[4,3-a][1]benzazepin-5-amine, [trans-4-(8-chloro-5-methoxy-5,6-dihydro-4H-[1,24]triazolo[4,3-a][1Ibenzazepin-1-yl)cyclohexyl | (4-methylpiperazin-1-yl)]methanone, (5R)-8-chloro-5-(morpholin-4-11)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1, 2 A4]triazolo[4,3-a][1 Ibenzazepine, N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4 ,3-a][1 Ibenzazepin-5-yl)acetamide, N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4, 3-a][1 Ibenzazepin-5-yl)-2-hydroxy1-2-methylpropanamide, 8-chloro-5-methoxy-1-[1-(tetrahydro-2H-pyran-4-11)piperidin-4-11])-5,6-dihydro-4H-[1,24] triazolo[4,3-a][1]benzazepine, 8'-chloro-1'-[4-(pyridin-2-yl)piperazin-1-11]-4'H,6'H-spiro[1, 3-dioxolane-2,5'-[1,24]triazolo[4,3-a][1]benzazepine], 8-chloro-1-(1'H,3H-spiro[2-benzofuran-14] '-piperidin]-1"-yl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-ol, 8-chloro-1 -[4-(3-chloropyridin-2-yl)piperidin-1-11]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepin- 5-hol, (5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5-(pyrrolidin-1-11)-5,6-dihydro-4H-[1, 2 4]triazolo[4,3-a][1 Ibenzazepine, 8-Chloro-5-methoxy-1-(1-[(3S)-tetrahydrofuran-3-yl Ipiperidin-4-11)-5,6-dihydro-4H-[1,2 A4]triazolo[4, 3-a][1]benzazepine, (5R)-8-fluoro-5-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[ 4,3-a][1]benzazepine, (55)-8-fluoro-S-methoxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[ 4,3-a][1]benzazepine, 8-Chloro-5-methoxy-1-[1-[(3R)-tetrahydrofuran-3-ylpiperidin-4-11)-5,6-dihydro-4H-[1,2A4]triazolo[4, 3-a][1]benzazepine, N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4 ,3-a][1]benzazepin-5-yl +-No. No. -dimethyl-B-alaninamide, N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4 ,3-a][1]|benzazepin-5-yl tetrahydro-2H-pyran-4-carboxamide, 8-chloro-1-[4-(pyridin-2-yloxy)piperidin-1-11]-5,6-dihydro-4H- [1,2 4]triazolo[4,3-a][1 Ibenzazepin-5-ol, 8-chloro-5-methoxy-1-[trans-4-(4-methylpiperazin-1-yl)cyclo- hexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepine, 8-chloro-S-methoxy-1-[cis-4-(4 -methylpiperazin-1-yl)cyclohexyl]- 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine, 8-chloro-5-methoxy-1-[1-(pyridin-3-ylmethyl) pyrrolidin-3-11]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine, 8-chloro-5-methoxy-1-[1- (pyridin-2-ylmethyl)pyrrolidin-3-11]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine, N-((5R) -8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][ 1]|benzazepin-5-11)-2-cyanoacetamide, [3-(8-chloro-5-methoxy-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a ][1]benzazepin-1-yl)pyrrolidin-1-yl |(pyridin-3-1l)]methanone, 8'-chloro-1'-(1-[(3R)-tetrahydrofuran-3-yl]piperidin-4 -11) - 4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]|benzazepine], [3- (8-chloro-5-methoxy-5,6-dihydro-4H-[1,24]triazolo[4,3-al[1]benzazepin-1-yl)pyrrolidin-1-yl](pyridin- 2-yl)]methanone, trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2A]triazolo[4,3- a][1]benzazepin]-1"-yl)-N,N-dimethylcyclohexanamine, 8-chloro-S-methoxy-1-(1'H,3H-spiro[2-benzofuran-1,4"- piperidin]-1"-11)-5,6-d i-hydro-4H-[1,24]triazolo[4,3-a][1]benzazepine, 8-chloro-1-[4-(3-chloropyridin-2-yl)piperazin-1-yl]- S5-methox1-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepine, N-[trans-4-(8'-chloro-4'H ,6'H-spiro[1,3-dioxolane-2.5"-[1,24]triazolo[4,3-a][1]Ibenzazepin]-1"-yl)cyclohexyl Ipyridin-2- amine, N'-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4] triazolo[4,3-a][1]benzazepin-5-yl |-N N-dimethylethane-1,2-diamine, 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclo acetate -hexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a][1]benzazepin-5-yl, 2-(1(5R)-8-chloro-1 -[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepin-5- yl]amino)ethanol, 8-chloro-S-methoxy-1-[4-(pyridin-2-yloxy)piperidin-1-11]-5,6-di- hydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine, 8'-chloro-1'-(trans-4-methoxy-4-methylcyclohex11)-4'H, 6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine], (5S)-8-chloro-N-(cyclopropylmethyl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24]triazole [4,3-a][1 |benzazepin-5-amine, N-((58)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4 ,3-a][1]|benzazepin-5-11)-1-methylpiperidine-4-carboxamide, N-((5S5)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,24]triazolo[4, 3-a][1 Ibenzazepin-5-11)-2,2,2-trifluoroacetamide, 8-chloro-5-(2-methoxyethoxy)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[ 4,3-a][1]benzazepine, 8-Chloro-1-(4-methoxy-4-methylcyclohexyl)-N-(propan-2-yl)-5,6-dihydro-4H-[1,2,A]triazolo[4,3 -a][1]benzazepin-5-amine, 8'-Chloro-1'-(trans-4-methoxy-4-methylcyclohexyl)-4'H,6'H-spiro[1,3-dioxane-2,5'-[1,2,4] triazolo[4,3-a][1]benzazepine], 8'-chloro-1"-(cis-4-methoxy-4-methylcyclohexyl)-4'H,6'H-spiro[1,3-dioxane-2,5'-[1,2,4] triazolo[4,3-a][1]benzazepine], 8-chloro-5-fluoro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3- a]|[1]benzazepine, 8-chloro-5-[2-(methylsulfonyl)ethoxy]-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2 A4] triazolo[4,3-a][1]benzazepine, 8-Chloro-N-hydroxy-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-4H-[1,24]triazolo[4,3-a][1Ibenzazepin-5(6H )-imine, (55)-8-chloro-N-methyl-N-(prop-2-yn-1-yl)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di -hydro-4H-[1,2A4]triazolo[4,3-a][1Ibenzazepin-5-amine, N-((55)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di- hydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-yl)-3,3-difluorocyclobutanecarboxamide, 8-chloro-5-(prop-2-yn-1- yloxy)-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1] benzazepine, 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a] [1]|benzazepin-5-yl-4,4-difluorocyclohexanecarboxylate, 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H -[1,2,A]triazolo[4,3-a][1]benzazepin-5-yl 3,3-difluorocyclobutanecarboxylate, N-((55)-8-chloro-1-[trans-4-(pyridin) -2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a][1|benzazepin-5-yl)-4,4-difluorocyclocyclohexane hexanecarboxamide, 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2A]triazolo[4,3-a][ 1]benzazepin-5-yl cyanoacetate, 8-chloro-1-[trans-4-(pyridin-2-1loxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazole [4,3-a][1]benzazepin-5-yl N,N-dimethylglycinate, N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl] -5,6-dihydro-4H-[1,2,4]triaz olo[4,3-a][1]benzazepin-5-11)-2,2,2-trifluoroacetamide, 1-[cis-4-(8-chloro-5-methox1-5,6-dihydro- 4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-yl)cyclohexylpyrrolidin-2-one, 1-[trans-4-(8-chloro-5-methox1] -5,6-dihydro-4H-[1,24]triazolo[4,3-a][1Ibenzazepin-1-yl)cyclohexyl|pyrrolidin-2-one, N-((5R)- 8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1 ]benzazepin-5-11)-3,3-difluorocyclobutanecarboxamide, N-((SR)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-di- hydro-4H-[1,2,A]triazolo[4,3-a][1]|benzazepin-5-yl)-4,4-difluorocyclohexanecarboxamide, 8-chloro-5-methoxy-1-[cis-4-methoxy-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,2,A4]triazolo[4,3- a][1]benzazepine, 8-chloro-5-methoxy-1-[trans-4-methoxy-4-(trifluoromethyl)cyclohexyl]-5,6-dihydro-4H-[1,24] triazolo[4,3-a][1]benzazepine, (5S)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]|-N-(2,2,2-trifluoroethyl)-5,6-dihydro-4H- [1,2 A4]triazolo[4,3-a][1]|benzazepin-5-amine, N-((58)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4 ,3-a][1]|benzazepin-5-11)-3-methyloxetane-3-carboxamide, N-((5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,4]triazolo[4 ,3-a][1 Ibenzazepin-5-11)-3-methyloxetane-3-carboxamide, trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'- [1,2 A]triazolo[4,3-a][1]benzazepin]-1"-11)-N-(4-methoxybenzyl)cyclohexanamine, [2-(1(5R)-8-chloro-1-[trans-4-(pyridin-2-yloxy)cyclohexyl]-5,6-dihydro-4H-[1,2,A]triazole [4,3-a][1]benzazepin-5-ylamino)ethyl]tert-butyl carbamate, 8'-Chloro-1"-(trans-4-ethoxy-4-ethylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,24]triazolo [4,3-a][1]benzazepine], trans-4-(8'-chloro-4'H,6'H-spiro[1,3-dioxolane-2,5'- [1,24]triazolo[4,3-a][1Ibenzazepin]-1"-yl)-N-(4-methoxybenzyl)-N-methylcyclohexanamine, 8'-Chloro-1'-[1-(pyridin-3-ylmethyl)pyrrolidin-3-11)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2] ,4]triazolo[4,3-a][1]benzazepine], 8-chloro-5-methoxy-1-[4-(pyridin-2-yl)piperazin-1-11]-5,6-dihydro-4H-[1,24]triazolo[4,3-a ][1]benzazepine, 8-Chloro-1-(trans-4-ethyl-4-methoxycyclohexyl)-N N-dimethyl-5,6-dihydro-4H-[1,2,A]triazolo[4,3-a] [1]benzazepin-5-amine, 8-chloro-1-(trans-4-ethoxy-4-methylcyclohexyl)-N,N-dimethyl-5,6-dihydro-4H-[1,2A]triazolo[4,3-a] [1]benzazepin-5-amine, 8'-chloro-1"-[trans-4-methoxy-4-(trifluoromethyl)cyclohexyl]-4'H,6'H-spiro[1,3-dioxolane- 2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine], 8'-chloro-1'-[cis-4-methoxy-4-(trifluoromethyl)cyclohexyl] - 4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine], 8'-chloro-1' -(trans-4-ethoxy-4-methylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a ][1]benzazepine], 8'-chloro-1'-(trans-4-ethoxy-4-propylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'- [1,2,4]triazolo[4,3-a][1]benzazepine], 8'-chloro-1"-[1-(pyridin-2-ylmethyl)pyrrolidin-3-11)-4'H, 6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepinal], 8'-chloro-1'-(cis-4 -ethyl-4-methoxycyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine ], 8'-chloro-1'-(trans-4-ethyl-4-methoxycyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2, 4]triazolo[4,3-a][1]benzazepine], 8'-cl oro-1"-(trans-4-methoxy-4-propylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4] ,3-a][1]benzazepine], 8'-chloro-1'-(cis-4-methoxy-4-propylcyclohexyl)-4'H,6'H-spiro[1,3-dioxolane-2 ,5'-[1,2,4]triazolo[4,3-a][1]benzazepine], 8-chloro-1-(trans-4-ethoxy-4-ethylcyclohexyl)-N-(propan- 2-yl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-5-amine, 8-chloro-1-(trans-4- ethoxy-4-ethylcyclohexyl)-N,N-dimethyl-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1 Ibenzazepin-5-amine, 8' -chloro-1"-[(3R)-1-(pyridin-2-ylmethyl)pyrrolidin-3-11)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1 ,2,4]triazolo[4,3-a][1]benzazepine], 8-chloro-5-methoxy-1-[(3R)-1-(pyridin-3-ylmethyl)pyrrolidin-3-11]- 5,6-dihydro-4H-[1,2,A]triazolo[4,3-a][1]benzazepine, 8-chloro-S-methoxy-1-[(3R)-1-(pyridin- 2-ylmethyl)pyrrolidin-3-yl]- 5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepine, 8'-chloro-1"-[(3S)-1-(pyridin-3- ylmethyl)pyrrolidin-3-11)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1]benzazepine] , 8'-Chloro-1'-[(3R)-1-(pyridin-3-ylmethyl)pyrrolidin-3-11)-4'H,6'H-spiro[1,3-dioxolane-2,5' -[1,2,4]triazolo[4,3-a][1]benzazepine], 8-chloro-5-methoxy-1-[(35)-1-(pyridin-3-ylmethyl)pyrrolidin-3- yl]-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1 Ibenzazepine, 8'-chloro-1"-[(3S)-1-(pyridin- 2-ylmethyl)pyrrolidin-3-11)-4'H,6'H-spiro[1,3-dioxolane-2,5'-[1,2,4]triazolo[4,3-a][1] benzazepine] and 8-chloro-5-methoxy-1-[(3S)-1-(pyridin-2-ylmethyl)pyrrolidin-3-yl]-5,6-dihydro-4H-[1,2, 4]triazolo[4,3-a][1 |benzazepine. 33. Pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound of general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or or racemate thereof and/or diastereomer thereof and/or biologically active metabolite thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof, as defined with either of claims 1 to 32, as an active substance and a pharmaceutically acceptable excipient. 34. Combination composition, characterized in that it comprises a therapeutically effective amount of a compound of general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and /or racemate thereof and/or diastereomer thereof and/or biologically active metabolite thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof, as defined with any one of claims 1 to 32, and one or more other active substances. 35. A combination composition as claimed in claim 34, characterized by the fact that one or more other active substances are selected from the group consisting of psycholeptics, psychoanaleptics, antihypertensives, spasmolytics, antiepileptics or other agents. A composition according to any one of claims 33 to 35, characterized in that it is for use in the treatment and/or prophylaxis of a disease or condition associated with central and/or peripheral Vla receptor antagonization. 37. Process for the preparation of a pharmaceutical composition having Vla receptor antagonist activity, characterized in that it comprises a therapeutically effective amount of a compound of general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active metabolite thereof and/or prodrug thereof and/or solvate thereof and/or hydrate of the same and/or polymorph thereof, as defined by any one of claims 1 to 32, as an active substance with pharmaceutically acceptable excipients. 38. Compound of general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or metabolite biologically active of the same and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof according to any one of claims 1 to 32, characterized in that it is for use in the treatment and/or prophylaxis of a disease or condition associated with central and/or peripheral Vila receptor antagonization. 39. A compound, characterized in that it is for use as defined in claim 38, wherein the disease or condition associated with central and/or peripheral Vla receptor antagonization is selected from the group consisting of various pathological conditions of the female sexual organs , long-term blood pressure control conditions, conditions resulting from inappropriate vasopressin secretion, anxiety, depression, aggression, central nervous system disorders where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autism spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavioral disorders and/or irritability, hyperactive behavioral disorders, cognitive disorders or other neuropsychiatric disorders. 40. Use of a compound of general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and /or biologically active metabolite thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof as defined with any one of claims 1 to 32, characterized in that it is for the treatment and/or prophylaxis of a disease or condition associated with central and/or peripheral Vla receptor antagonization. 41. Use according to claim 40, characterized in that the disease or condition associated with central and/or peripheral Vla receptor antagonization is selected from the group consisting of various pathological conditions of the female sexual organs, conditions in long term permanence of blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavior disorders and/or irritability, hyperactive behavioral disorders, cognitive disorders or other neuropsychiatric disorders. 42. A method for treating and/or preventing a disease or condition associated with Vla receptor function, comprising administering to the mammal to be treated a therapeutically effective amount of a compound of formula (1) and/or or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or biologically active metabolite thereof and/or prodrug thereof same and/or solvate thereof and/or hydrate thereof and/or polymorph thereof, as defined in any one of claims 1 to 32, alone or with pharmaceutically acceptable excipients. 43. Method according to claim 42, characterized in that the disease or condition associated with central and/or peripheral Vla receptor antagonization is selected from the group consisting of various pathological conditions of the female sexual organs, conditions in long term permanence of blood pressure control, conditions resulting from inappropriate secretion of vasopressin, anxiety, depression, aggression, disorders of the central nervous system where one of the symptoms and/or syndromes of the disease may be related to anxiety, depression, aggression or show comorbidity with them (autistic spectrum disorder, obsessive compulsive disorder, various forms of Down syndrome, post-traumatic stress disorder), aggressive behavior disorders and/or irritability, hyperactive behavioral disorders, cognitive disorders or other neuropsychiatric disorders. 44. Compound, characterized by the general formula (1) and/or salt thereof and/or geometric isomer thereof and/or stereoisomer thereof and/or enantiomer thereof and/or racemate thereof and/or diastereomer thereof and/or or biologically active metabolite thereof and/or prodrug thereof and/or solvate thereof and/or hydrate thereof and/or polymorph thereof, as defined in any one of claims 1 to 32, and one or more of the others active substances for use in the treatment and/or prophylaxis of a disease or condition associated with central and/or peripheral Vla receptor antagonization. 45. Combination, characterized in that it is for use as defined in claim 44, wherein one or more other active substances are selected from the group consisting of psycholeptics, psychoanaleptics, antihypertensives, spasmolytics, antiepileptics or other agents. 46. Compound, characterized in that it is of formula (XIII), in which R' is chlorine or bromine N. NHBoc wool, 47. Compound, characterized in that it is of formula (III), wherein R' is chloro or bromo N. NHBoc wool, 48. Compound, characterized in that it is of formula (IV-a), tert-(7-chloro-2-(methylsulfanyl)-4,5-dihydro-3H-1-benzazepin-4-yl)carbamate butyl" CO NHBoc, 49. Compound, characterized in that it is of formula (XXI), where R! is it chlorine or bromine H o Lc 1 o SO. 50. Compound, characterized in that it is of formula (XXV), 4-([tert-butyl(dimethyl)silylJoxy)-7-chloro-1,3,4,5-tetrahydro-2H-1-benzazepin -2-one H or N.- THERE SN 51. Compound, characterized in that it is of formula (III-b), 4-([tert-butyl(dimethyl)silylJoxy)-7-chloro-1,3,4,5-tetrahydro-2H- 1- benzazepin-2-thiona Y Ss LO END 52. Compound, characterized in that it is of formula (XLIV), 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one H o N. LO o—. 53. Compound, characterized in that it is of formula (II-c), a 7-chloro-4-methoxy-1,3,4,5-tetrahydro-2H-1-benzazepine-2-thione H Ss N . LO o—.